Metabolic and regulatory adaptations of Staphylococcus epidermidis to host stresses

Authors: Sandra M Carvalho, Lígia M Saraiva

Abstract

Staphylococcus epidermidis is a highly adapted commensal of the human skin. However, it can also cause severe infections by exploiting skin fissures to establish antibiotic-resistant biofilms on implanted medical devices, which may subsequently release bacteria into the bloodstream. Emerging studies increasingly highlight the critical role of metabolic status and regulatory mechanisms in governing biofilm formation and, consequently, the pathogenic potential of S. epidermidis. This review examines its metabolic adaptability across different environments, emphasizing how environmental factors such as nutrient availability, oxygen levels, pH, and temperature, shape central metabolic pathways. It covers sugar, amino acid, and fatty acid utilization, regulatory networks controlling respiration, fermentation, and polysaccharide intercellular adhesin (PIA)-mediated biofilm formation, and strategies for surviving host-derived oxidative and nitrosative stresses. Comparisons with S. aureus further reveal species-specific differences in metabolism, nutrient acquisition, and regulation. Altogether, the mechanistic insights provide a comprehensive overview of S. epidermidis physiology in both commensal and infection-associated contexts.

Introduction

Staphylococcus epidermidis is a Gram-positive, facultative anaerobic bacterium classified as a coagulase-negative Staphylococcus (CoNS). It is a common commensal of the human skin and mucosal surfaces, including the nasal cavity. Although generally harmless, S. epidermidis is a major opportunistic pathogen in hospital settings, particularly in association with indwelling medical devices. In the United States, central line-associated bloodstream infections (CLABSIs), which are serious infections that occur when bacteria or other pathogens enter the bloodstream via a central line such as a catheter placed in a large vein, are frequently caused by coagulase-negative staphylococci. These organisms account for ∼17% of CLABSI cases in adults and ∼19% in neonates, in intensive care units (ICUs), according to the 2018–2021 data from the CDC’s (Centre for Disease Control and Prevention) National Healthcare Safety Network (NHSN). In Europe, the most frequently isolated microorganisms in hospital episodes of bloodstream infections (BSI) in ICUs, including microbiologically confirmed catheter-related BSIs, were coagulase-negative staphylococci (ECDC, Healthcare-associated Infections Acquired in Intensive Care Units, Annual Epidemiological Report for 2021). Among these infections S. epidermidis is the most representative species.

S. epidermidis cells originating from the skin can adhere to the material surfaces in deep tissues, initiating biofilm formation. These biofilms are bacterial communities embedded in an extracellular polymeric substance (EPS) matrix composed of polysaccharides (e.g. polysaccharide intercellular adhesin, PIA), proteins, and extracellular DNA. S. epidermidis produce biofilms consisting of surface-associated proteins (protein-based biofilms) and/or PIA-based matrices, the latter synthesized by the icaADBC operon and critical for immune evasion and persistent colonization (Vuong et al. 2004c, Heilmann et al. 1996, Ziebuhr et al. 1999, Rohde et al. 2005, Sun et al. 2005, Schommer et al. 2011, Paharik et al. 2017). In general, biofilm formation occurs in three attachment, maturation, and dispersal. Mature biofilms contribute to immune evasion, antibiotic resistance, and facilitate horizontal gene transfer. S. epidermidis can carry the methicillin resistance gene mecA on the mobile element SCCmec, which may be transferred to other bacteria, such as S. aureus (Hanssen and Ericson Sollid 2006, Bloemendaal et al. 2010, Smyth et al. 2011, Altayb et al. 2022, Maree et al. 2022). Cells from mature biofilms can detach and survive as planktonic form in blood leading to bacteraemia and bloodstream dissemination. Thus, the progression of S. epidermidis infection begins with skin colonization, followed by adherence and biofilm formation on medical devices, and ultimately dissemination into the bloodstream.

For a detailed understanding of biofilm biology, associated virulence mechanisms, clinical implications, and anti-biofilm strategies, readers are directed to several comprehensive review articles (Otto 2009, Fey and Olson 2010, Gomes et al. 2014, Namvar et al. 2014, Otto 2018, Schilcher and Horswill 2020, Joubert et al. 2022, Skovdal et al. 2022, Severn and Horswill 2023, Siciliano et al. 2023).

S. epidermidis is metabolically versatile, possessing complete Embden–Meyerhof–Parnas (EMP), pentose phosphate (PPP), and tricarboxylic acid (TCA) pathways (Gill et al. 2005). It also harbors electron transport chain (ETC) components that enable both aerobic and anaerobic respiration (Gill et al. 2005, Uribe-Alvarez et al. 2016).

Under aerobic conditions, S. epidermidis relies on aerobic respiration to grow (Pedroza-Dávila et al. 2020, Oliveira et al. 2023). Aerobic respiration is widely associated with the planktonic growth state of S. epidermidis (Yao et al. 2005, Cotter et al. 2009b, Bottagisio et al. 2019). Consequently, most studies investigating planktonic S. epidermidis employ fully aerobic liquid culture conditions in laboratory experiments (Yao et al. 2005, Cotter et al. 2009b, Wu et al. 2015, Bottagisio et al. 2019, Pedroza-Dávila et al. 2020, Oliveira et al. 2023).

Under oxygen-limited conditions, S. epidermidis performs anaerobic respiration and/or fermentation, during which glycolysis remains active while the oxidative TCA cycle activity may be low and carbon redirected into alternative pathways. Although there is a putative gene encoding fumarate reductase-like enzyme in S. epidermidis genome, a canonical multi-subunit fumarate reductase as found in E. coli (encoded by frdABCD) is not present, and there is no experimental evidence that S. epidermidis can use a partial reverse or reductive TCA cycle under anaerobic conditions (Himpsl et al. 2020, Pedroza-Dávila et al. 2020, Martínez-García et al. 2021, Calvo et al. 2022, Oliveira et al. 2023). The type of metabolism observed under oxygen-limiting conditions is particularly relevant during S. epidermidis biofilm formation, as oxygen diffusion becomes progressively restricted with increasing biomass. Early biofilm stages are characterized by a decrease in metabolic activity (Vandecasteele et al. 2004, Cotter et al. 2009a), with downregulation of PPP, TCA, and aerobic ETC pathways and upregulation of glycolytic, fermentative, and anaerobic components (Yao et al. 2005, Uribe-Alvarez et al. 2016, Pedroza-Dávila et al. 2020, Martínez-García et al. 2021, Calvo et al. 2022).

In this review, we summarize current understanding of the physiological environments that S. epidermidis encounters on the skin and in deeper tissues, and in bloodstream (section Physiological, nutritional, and oxygen conditions encountered by S. epidermidis in host niches, Table 1). We further describe metabolic adaptations that can be relevant to planktonic versus biofilm-associated lifestyles (section Transport and metabolism in S. epidermidis). We focus on the transport and catabolism of key nutrients—including sugars, amino acids, and fatty acids—and the modulatory role of oxygen availability on these pathways and biofilm formation (section Transport and metabolism in S. epidermidis). Section Transcriptional control of S. epidermidis metabolism covers major metabolic regulators, with a focus on those controlling respiration, fermentation, and the biosynthesis of PIA, the principal exopolysaccharide component of the biofilm matrix. In section Adaptation strategies of S. epidermidis to host environmental challenges, we discuss the strategies employed by S. epidermidis to withstand host-derived oxidative and nitrosative stress, as well as thermal and acidic challenges. Finally, section Metabolic divergences between S. epidermidis and S. aureus outlines key metabolic differences between S. epidermidis and S. aureus.

Table 1 presents an overview of S. epidermidis phenotypic characteristics, including its ability to adhere and form biofilms across the different niches (skin, deeper tissues/medical devices, and blood) as well as the specific environmental conditions associated with each niche. Table 2 describes the characteristics of the strains referenced in this review.

Physiological, nutritional, and oxygen conditions encountered by S. epidermidis in host niches

Staphylococcus epidermidis changes its metabolism during the transition from skin surface colonization to biofilm formation on medical devices, and ultimately to invasive, life-threatening bloodstream infections. Understanding how this bacterium shifts its metabolic strategies in response to environment is central to unravelling the mechanisms underlying its pathogenic potential. In this section, we describe the distinct environmental conditions encountered by S. epidermidis in the skin (section Skin), deeper tissues and bloodstream (section Deeper tissues and blood), focusing on the major carbon sources available and oxygen conditions. These niche-specific environmental conditions modulate the organism’s metabolic adaptation, which is examined in more detail in section Transport and metabolism in S. epidermidis.

Skin

The skin is the primary colonization niche of S. epidermidis. While S. epidermidis is also capable of colonizing the nasal cavity, this site is not regarded as a main route of transition to infection and will therefore not be addressed in this review.

Within the complex structure of the skin, S. epidermidis cells inhabit a variety of microenvironments, including dry, moist, sebaceous, and foot regions (Chia et al. 2025).

It predominantly resides in the stratum corneum, the outermost layer of the epidermis, which consists mainly of dead, keratinized cells and presents a dry, nutrient-limited environment. The bacterium also colonizes deeper structures such as hair follicles, which are associated with sebaceous glands, and sweat glands, both located in the superficial dermis (Byrd et al. 2018, Severn and Horswill 2023).

Oxygen gradients in the skin arise from its uneven vascularization—the dermis and hypodermis are vascularized, but the epidermis is not—as well as from the limited diffusion of oxygen from the atmosphere through the epidermis. As result, oxygen concentrations range from low (0.1–2.5%, average ∼1%) in the basal epidermis, hair follicles, and sebaceous glands, to moderate levels (up to 7%) in the superficial epidermis and hypodermis, which remain substantially below atmospheric levels (21%) (Chettouh-Hammas and Grillon 2024) (Table 1). These oxygen-limited dermal structures favour fermentative metabolism by the resident microbiota.

Skin-resident organisms such as S. epidermidis are adapted to utilize alternative carbon and energy sources available in the skin’s unique environment, which is largely composed of sebum and sweat (Table 1).

Nutritionally, the skin provides a poor environment for most bacteria because it lacks significant amounts of readily utilizable carbon sources such as common carbohydrates like glucose, fructose, and sucrose, which bacteria typically use for rapid growth in nutrient-rich or fermentative conditions (Kumar et al. 2019). A variety of other sugars, including trehalose, maltose, gluconate, mannitol, sorbitol, and pentitol, are also present in trace amounts in skin tissues or may be introduced exogenously via food residues, personal care products, detergents, and cosmetics (Espadinha et al. 2019).

Coating the skin and supporting its barrier function, the sebum from sebaceous glands is rich in lipids like triglycerides and cholesterol, which, when hydrolyzed by bacterial lipases in the sebaceous duct, release free fatty acids and glycerol that serve as substrates for microbial metabolism (Picardo et al. 2009, Wertz 2018, Vietri Rudan and Watt 2022, Swaney et al. 2023, Isom and Desaire 2024).

Sweat, produced by both eccrine and apocrine glands, is primarily composed of water and electrolytes, but also contains small quantities of fatty acids, glycerol, urea, lactic acid and amino acids, such as the branched-chain amino acids valine, leucine, and isoleucine (Choi et al. 2005, Kumar et al. 2019). These compounds contribute to the acidic pH of the skin (pH ∼5), to which S. epidermidis is well adapted for growth (Iyer et al. 2021 , Gonçalves et al. 2022).

Recent studies using artificial skin media have shown that S. epidermidis strains isolated from the skin of healthy volunteers grow better when exposed to higher concentrations of sweat, while their growth remains relatively uniform across varying levels of sebum. However, the specific components in sweat responsible for this concentration-dependent growth enhancement of S. epidermidis remain to be identified (Swaney et al. 2023).

Transcriptomic studies demonstrated that during asymptomatic colonization of healthy human skin, resident non-typed S. epidermidis strains exhibited strong upregulation of sphingomyelinase—an enzyme that cleaves sphingomyelin into phosphocholine and ceramide—thereby releasing nutrients and contributing to skin barrier function (Teichmann et al. 2022, Zheng et al. 2022). Furthermore, TCA cycle genes such as fumC (fumarate hydratase), gltA (citZ citrate synthase), and icd (isocitrate dehydrogenase) were expressed at low levels in S. epidermidis residing on healthy toe skin, consistent with limited oxygen availability or reflecting a very specific microenvironment that is rich in nutrients, where typically the TCA cycle is not fully activated (Teichmann et al. 2022).

Deeper tissues and blood

Under healthy conditions, S. epidermidis cells remain confined to the surface of the skin and do not penetrate deeper layers such as the dermis and hypodermis. However, during their transition to a pathogenic state, they can be detected in these vascularized tissues, particularly when the host immune response is compromised, the skin barrier is disrupted (e.g. due to wounds), or when medical devices are implanted within the dermis or subcutaneous tissue. These deeper layers are enriched with blood serum-derived metabolites, including amino acids, lipids, lactate, urea, creatinine, and glucose, which can serve as nutrient sources (Table 1). Glucose is the predominant carbon source in blood, which is typically present at concentrations ranging from ∼4–6 mM under fasting conditions, and rising to ∼10 mM in states of hyperglycemia (Wahjudia et al. 2010, Benjamin et al. 2024). Glucose is also a carbon source that supports higher growth rates and cell densities in many bacteria of the phylum Firmicutes, including S. epidermidis (Bidossi et al. 2012, Vitko et al. 2016, Benjamin et al. 2024).

In the reticular dermis and hypodermis, low to moderate oxygen availability (Chettouh-Hammas and Grillon 2024) establishes microaerobic conditions, which may facilitate the adhesion of planktonic S. epidermidis cells to implanted biomaterials, and consequently biofilm formation. Indeed, under reduced oxygen concentrations S. epidermidis shifts toward biofilm formation (Uribe-Alvarez et al. 2016, Pedroza-Dávila et al. 2020). As the biofilm develops, oxygen diffusion through the extracellular matrix becomes progressively restricted, resulting in hypoxic and, in some regions, anoxic microenvironments (Stewart and Franklin 2008) (Table 1). During the dispersal phase, S. epidermidis biofilms release planktonic cells into the bloodstream (França et al. 2016a). These circulating cells may subsequently adhere to new surfaces and establish secondary biofilms at distant tissue sites. Although no study has directly demonstrated that glucose is the primary carbon source used by S. epidermidis in blood, or compared the planktonic growth of S. epidermidis on different carbon sources, it is generally assumed that glucose supports bacterial proliferation in the bloodstream because it is more readily utilizable and present at higher concentrations than other carbon sources (Ivanisevic et al. 2015).

While the association between oxygen limitation and biofilm formation is well documented and supported by multiple studies referred in this review, the oxygen environment experienced by S. epidermidis during planktonic growth in vivo remains poorly defined. This uncertainty likely stems from the absence of a clear definition in the literature of whether skin-resident S. epidermidis populations are fully planktonic, fully sessile, or may exist in both states, as well as from the considerable heterogeneity of skin microenvironments and the limited information on whether these niches allow growing free-floating cells, which is the strict definition of planktonic growth. Several approaches including ex vivo human skin models inoculated with S. epidermidis and high-fidelity tissue super-resolution imaging would probably be required to clarify the true physiological state(s) of S. epidermidis on the skin. Similar uncertainty exists for bacterial cells disseminating into the bloodstream. Because most oxygen in blood is bound to haemoglobin, and only ∼2% is present as dissolved O₂, it is unclear how much oxygen is directly available to invading bacteria. Although oxygen is released from haemoglobin into tissues, and blood is a chemostat like environment, the effective oxygen tension encountered by bacteria in the blood has not been precisely defined. Evidence from other pathogens suggests that bloodstream environments may favour anaerobic metabolism. For example, Pettersen and co-workers (Pettersen et al. 2016) reported that Escherichia coli isolates purified from human blood cultures of septic patients, showed increased abundance of proteins associated with anaerobic and fermentative metabolism relative to aerobic growth on nutrient-rich or nutrient-limited solid media. Despite this, most studies of planktonic S. epidermidis rely on fully aerobic liquid culture, which may not accurately reproduce the oxygen levels encountered in vivo. In our perspective, a better understanding of the true oxygen conditions experienced by S. epidermidis during skin colonization and bloodstream dissemination and of its form is essential to determine whether current experimental settings accurately model in vivo physiology.

Transport and metabolism in S. epidermidis

S. epidermidis demonstrates the capacity to grow in a wide variety of host-derived nutritional environments, reflecting the versatility of its metabolic pathways. However, experimental data on the metabolism of many alternative carbon and nitrogen sources remain limited. This section summarizes the current knowledge on how S. epidermidis transports and metabolizes substrates critical for survival and adaptation during its shift from commensalism to pathogenicity, focusing on substrates that are both abundant in these environments and serve as carbon and energy sources, including sugars, such as sugar alcohols and organic acids (section Sugars, sugar alcohols, and organic acids), and amino acids (section Amino acids). Although fatty acids are not used as sole carbon sources by S. epidermidis, they are prevalent on the skin and play important roles in membrane stability, stabilization of respiratory complexes, and adaptation to environmental stress. These functions will be addressed in section Lipids and fatty acids.

Sugars, sugar alcohols, and organic acids

Glycerol, a sugar alcohol, and lactate, an organic acid, are two compounds naturally present on the human skin that may serve as carbon sources for S. epidermidis in its commensal state (Table 1). Indeed, non-typed skin-resident S. epidermidis strains and S. epidermidis ATCC 12228 isolated from healthy skin (biofilm^−^ and ica^−^) were shown to use glycerol and lactate as carbon sources, respectively (Zhang et al. 2003, Wang et al. 2014, Kumar et al. 2019). Moreover, catheter-sepsis isolates of S. epidermidis, strains RP62A and 1457 (biofilm^+^ and ica^+^, PIA matrix), encode genes for lactate and glycerol transporters (Gill et al. 2005, Galac et al. 2017). S. epidermidis strains isolated from the human skin microbiome were able to ferment ^13^C₃-glycerol under anaerobic conditions producing short-chain fatty acids (SCFAs) including acetic, butyric, lactic, and succinic acids (Wang et al. 2014). As well, carbon-rich cosmetic compounds such as cetearyl isononanoate (CIN) and PEG8-laurate are fermented by S. epidermidis ATCC 12228 into SCFAs (Marito et al. 2020, Negari et al. 2021). Among SCFAs, succinic and butyric acids have shown notable antimicrobial activity against S. aureus and Cutibacterium acnes, the principal bacteria responsible for acne vulgaris, presumably by lowering the intracellular pH (Shu et al. 2013, Wang et al. 2014, Negari et al. 2021). These findings position S. epidermidis as a promising probiotic for maintaining skin health in healthy individuals, while SCFAs emerge as potential prebiotic molecules. Moreover, glycerol, a common moisturizing agent in skincare products, also functions as a prebiotic substrate (Wang et al. 2014).

In S. epidermidis ATCC 12228 grown in test tubes in TSB medium containing sodium-L-lactate, volatile compounds were detected when comparing with cells grown without sodium-L-lactate, suggesting consumption/import of L-lactate as carbon source and conversion of lactate into pyruvate (Kumar et al. 2019). Volatile compounds such as diacetyl and 2,3-butanediol result from the activity of α-acetolactate synthase (ALS) on pyruvate. ALS mediates the condensation of two pyruvate molecules to form α-acetolactate, which can either undergo non-enzymatic oxidative decarboxylation to generate diacetyl or be enzymatically decarboxylated to acetoin. In turn, acetoin may be further reduced to 2,3-butanediol in the presence of NADH (Carvalho et al. 2017) (Fig. 1A). The inhibition of ALS activity by 5-hydroxymethylfurfural (5-HMF) effectively suppresses the formation of both diacetyl and 2,3-butanediol compounds, implicated in the generation of skin malodours (Kumar et al. 2019).

The sugars trehalose, maltose, gluconate, mannitol, sorbitol, and pentitol are present in the skin at much lower concentrations than major metabolites like glycerol and lactate, and their roles are less well characterized (Pinnagoda et al. 1990, Choi et al. 2005, Fluhr et al. 2008, Espadinha et al. 2019). S. epidermidis genomes encode transporters for gluconate and trehalose (Gill et al. 2005), and transcriptomic studies revealed that genes involved in the metabolism of these sugars were upregulated in S. epidermidis lineage B (primarily associated with skin colonization) and lineages A/C (associated with both colonization and infection) (Espadinha et al. 2019). A recent study showed that S. epidermidis ATCC 12228 grows in minimal medium using trehalose as the sole carbon source (Leonidou et al. 2025). This finding is particularly noteworthy because the inability to ferment trehalose has been considered a phenotypic hallmark of S. epidermidis, which was used to distinguish it from other bacterial species (Kloos and Schleifer 1975, Espadinha et al. 2019). Therefore, these results suggest a functional role of trehalose and gluconate in this bacterium.

S. epidermidis lacks genes encoding transporters for several sugars such as sorbitol, pentitol, maltose, and mannitol (Gill et al. 2005). Of note, the inability to ferment mannitol is a classic phenotypic trait used to differentiate S. epidermidis from S. aureus, which metabolises mannitol. Despite the absence of the canonical ABC-type maltose transporter, a S. epidermidis strain, isolated from a milk powder manufacturing plant, and exposed to maltose showed enhanced biofilm formation and bacterial viability, suggesting the existence of alternative, yet unidentified, maltose uptake systems and/or maltose-degrading enzymes (Zou and Liu 2020).

For sugars other than glucose, present in the bloodstream at low concentrations and lacking preferential transport mechanisms, no specific transporters have been conclusively identified. However, S. epidermidis RP62A encodes putative phosphotransferase systems (PTS) that may facilitate the transport of lactose, fructose, sucrose, and N-acetylglucosamine (Gill et al. 2005). Interestingly, when S. epidermidis strain 19 N grows aerobically at blood pH in TSB peptide-rich medium, which contains 2.5 g/l glucose (∼14 mM), the bacterium produces fructose- and sucrose-PTS systems (Gonçalves et al. 2022). Furthermore, the S. epidermidis strain obtained from a milk powder processing plant exhibited enhanced viability and biofilm production when grown in the presence of sucrose, fructose, and lactose, which suggests that these metabolites are effectively utilized by the bacterium (Zou and Liu 2020).

In relation to glucose, while genomic analysis of S. epidermidis strain RP62A identified a phosphoenolpyruvate-PTS and a symporter-type glucose transporter (Gill et al. 2005), the full repertoire of glucose transporters in S. epidermidis remains to be functionally characterized.

A glucose-specific PTS has been identified and found to be upregulated in proteomic analyses done under aerobic conditions for S. epidermidis strain ATCC 12228 lacking saeR, which encodes a two-component transcriptional regulatory system and oxygen sensor (Handke et al. 2008, Lou et al. 2014).

Similarly, upregulation of the glucose-PTS was observed in the aerobically grown S. epidermidis strain 19 N—an isolate from healthy anterior nares, biofilm^+^, and ica^+^ strain—when exposed to a blood-like pH of 7.4 (Gonçalves et al. 2022) (Fig. 1A). Other studies in S. epidermidis ATCC 12228 showed that glucose transport may occur through the glucose/H^+^ symporter, aka GlcPSe, a member of the major facilitator superfamily (Iancu et al. 2013, Santos Seica et al. 2020) (Fig. 1A). This transporter exhibits high specificity in a H⁺-dependent manner and shares significant amino acid sequence similarity with human GLUT and SLC2 glucose transporters (Bazzone et al. 2017, Santos Seica et al. 2020).

In most microorganisms capable of switching between aerobic respiration, anaerobic respiration, or fermentation, the oxygen availability influences glucose metabolism. We next describe the S. epidermidis distinct pathways of glucose metabolism under aerobic (section Staphylococcus epidermidis aerobic pathways of glucose metabolism), fermentative (section Glucose metabolism in S. epidermidis under fermentative conditions), and anaerobic respiratory conditions (section Glucose metabolism in S. epidermidis under anaerobic nitrate respiration), taking into account that in this bacterium, aerobic respiration predominantly supports planktonic growth (section Staphylococcus epidermidis aerobic pathways of glucose metabolism, Fig. 1A), whereas fermentative metabolism favours biofilm formation (section Glucose metabolism in S. epidermidis under fermentative conditions, Fig. 1A). Although anaerobic respiration also occurs in the absence of oxygen, it does not favour biofilm formation to the same extent as fermentative metabolism, which may explain the limited number of studies on S. epidermidis under this condition. Specifically, while end-product metabolites of glucose metabolism in S. epidermidis in anaerobic respiratory conditions have been analyzed, data on proteomic, transcriptomic, and regulatory aspects remain scarce.

Staphylococcus epidermidis aerobic pathways of glucose metabolism

In bacteria cells grown aerobically, the glucose catabolism generates pyruvate, via glycolysis (EMP pathway), that is primarily oxidized to acetyl-CoA by the pyruvate dehydrogenase complex (PDHc). This enzyme complex has been detected in proteomic studies of S. epidermidis strain 1984 (biofilm^+^, ica^+^, isolated from an ocular infection) under planktonic growth, but not under biofilm-forming conditions (Martínez-García et al. 2021) (Fig. 1A). In several strains of S. epidermidis (1457, RP62A, and 19 N), acetyl-CoA is subsequently directed into TCA cycle, converted to acetate via the phosphotransacetylase-acetate kinase (Pta-AckA) pathway, or reduced to lactate through fermentative metabolism, which indicates that fermentation occurs even under aerobic conditions (Gonçalves et al. 2022, Oliveira et al. 2023) (Fig. 1A). This is not surprising, as S. epidermidis must rapidly adapt to fluctuating environmental conditions, particularly during the transition to biofilm form where oxygen availability becomes limited.

Proteomic analysis of S. epidermidis strain 1984 cultured under aerobic, planktonic conditions revealed the expression of several TCA cycle-related enzymes, including CitZ (citrate synthase), AcnA (aconitase), OgdH (α-ketoglutarate dehydrogenase), SucBCD (succinyl-CoA synthetase and associated co-factors), and Sdh (succinate dehydrogenase), whereas these enzymes were not detected when the bacteria were grown under biofilm-forming conditions (Fig.1A) (Martínez-García et al. 2021). Another study demonstrated that the enzymatic activities of aconitase and isocitrate dehydrogenase are detectable early during the growth of S. epidermidis 1457, with their activities increasing significantly throughout the exponential phase (Fig. 1A) (Vuong et al. 2005). Consistent with these findings, the aconitase mutant (S. epidermidis 1457∆acn) exhibited a reduced growth rate during the exponential phase, accompanied by delayed glucose consumption, decreased intracellular ATP and NAD⁺ levels, and inability to utilize extracellular acetate that accumulates during exponential growth. Consequently, this acetate remains unconsumed in the post-exponential phase after glucose depletion (Sadykov et al. 2008). Inactivation of aconitase resulted in the intracellular accumulation of several upstream TCA cycle intermediates, particularly citrate, along with a decrease in succinate production during the exponential phase, which indicates that the TCA cycle is active during exponential growth (Sadykov et al. 2008).

The PDHc and the oxidative branch of the TCA cycle generate reducing equivalents (NADH, FADH₂) (Fig. 1A), which fuels the electron transport chain for ATP synthesis through oxidative phosphorylation. In general, these reducing equivalents are regenerated at the level of NADH dehydrogenases, which transfer electrons to menaquinone. Alternatively, electrons can be donated directly to menaquinone by other quinone-oxidoreductases. Proteomic profiling of S. epidermidis 19 N cells, cultivated under physiological blood pH conditions in TSB, identified the expression of a NADH:flavin oxidoreductase, succinate dehydrogenase (SdhA), and glycerol-3-phosphate dehydrogenase (G3Pdh) quinone-oxidoreductases (Fig. 2A). From menaquinone, electrons are transferred directly to terminal oxygen reductases, aka quinol oxidases. The quinol oxidase aa3 (cytochrome aa3 encoded by qoxBACD) was produced in S. epidermidis 19 N cells grown aerobically at blood pH (Gonçalves et al. 2022) (Fig. 2A). Additionally, homologs of quinone oxidoreductase Mqo, succinate dehydrogenase (SdhA), and the terminal oxidase cytochrome  aa3 were identified via proteomic studies of planktonic cells of S. epidermidis strains 1984 and 1457 grown in TSB supplemented with glucose (Martínez-García et al. 2021).

In low glucose containing medium, such as in LB, the respiratory chain of S. epidermidis is similar to that on TSB glucose medium, except for the presence of quinone oxidoreductases (Lqo), which consume lactate, and cytochrome bo. Specifically, mass spectrometry following native electrophoresis of protein extracts from aerobically LB-grown S. epidermidis ATCC 12228 cells revealed NADH dehydrogenase type II (NDH-2), NADH:flavin oxidoreductase, G3Pdh, Sdh, Mqo1, and Lqo (Spahich et al. 2016, Uribe-Alvarez et al. 2016) (Fig. 2A). Additionally, differential absorbance spectra of membranes extract from the same cultures showed peaks for cytochromes aa3 and bo, while for cytochrome bd and cytochrome c were not detected (Uribe-Alvarez et al. 2016).

Physiological lactate concentrations in blood (typically ∼1–2 mM) are significantly lower than glucose levels (∼4–6 mM) and much lower than those found in skin sweat, where lactate can range from ∼2 to 30 mM (Petersen 1999, Luo et al. 2021). Although lactate is typically associated with microaerobic or hypoxic environments, and is an end-product of fermentative metabolism, it can also serve as a metabolic substrate in different species, including S. epidermidis strains ATCC 12228 and RP62A when grown under aerobic conditions (Spahich et al. 2016, Pedroza-Dávila et al. 2020). In S. epidermidis RP62A, Mqo1 and three quinone oxidoreductases (designated Lqo1, Lqo2, and Lqo3) were characterized based on their ability to utilize malate and L-lactate, respectively (Spahich et al. 2016). Notably, when lactate is the primary substrate, it supports a higher rate of oxygen consumption in the respiratory chain than glucose, likely due to the direct transfer of electrons to menaquinone via these oxidoreductases (Pedroza-Dávila et al. 2020).

Moreover, aerobic cultures of S. epidermidis ATCC 12228 treated with cyanide, an inhibitor of cytochromes aa3 and bo (but not of cytochrome bd), was reported to inhibit oxygen consumption and stimulate biofilm formation (Uribe-Alvarez et al. 2016). These findings are in accordance with the presence in S. epidermidis strains of active respiratory chains where electrons from quinone-oxidoreductases are transferred to menaquinone, and then donated to terminal oxygen reductases, namely the quinol oxidases cytochromes aa3 and bo (Uribe-Alvarez et al. 2016). Although S. epidermidis genomes contain cydAB genes, the conditions that induce expression and functional assembly of the cytochrome bd complex remain unidentified (Fig. 2) (Gill et al. 2005, Uribe-Alvarez et al. 2016). Therefore, a detailed characterization of S. epidermidis respiratory chain components remains to be done.

Glucose metabolism in S. epidermidis under fermentative conditions

Aerobic respiration underpins planktonic growth in S. epidermidis (section Staphylococcus epidermidis aerobic pathways of glucose metabolism, Fig. 1A), whereas glucose fermentative metabolism predominates in biofilms (Fig. 1A). Under low-oxygen and biofilm-forming conditions, glucose yields two molecules of pyruvate and only two molecules of ATP via substrate-level phosphorylation (EMP). This ATP yield is far lower than that obtained from aerobic respiration (up to 38 ATP per glucose molecule), making glycolysis the primary source of energy in biofilms. To sustain this flux, the NADH generated during glycolysis must be continuously regenerated to NAD^+^, a process carried out mainly by lactate dehydrogenases (LDHs), which reduce pyruvate to lactate (Fig. 1A). Consequently, LDHs have a central role in maintaining energy metabolism and supporting biofilm growth and persistence. S. epidermidis, like many other bacterial species, produce the two stereoisomers of lactic acid, i.e. L-lactate and D-lactate, through the activity of one L-LDH and one D-LDH (Morovic et al. 2024). Besides lactate, S. epidermidis strains RP62A and 1457 also produce acetate as end-product from pyruvate via the phosphotransacetylase (Pta) and acetate kinase (AckA) pathway, although at a significantly lower extent (Oliveira et al. 2023) (Fig. 1A). When pyruvate analogues that inhibit its conversion to lactate, such as oxamate, are used, the S. epidermidis RP62A and 1457 metabolism shifts toward acetate production, leading to increased acetate levels and a reduction in biofilm mass, thereby highlighting the critical role of the lactate pathway in biofilm formation (Oliveira et al. 2023). The conversion of pyruvate to acetate is coupled to ATP generation and provides additional means of energy production under hypoxic conditions (Fig. 1A). Minor fermentation end-products, such as formate, succinate, ethanol, acetoin and 2,3-butanediol are also detected extracellularly, the last three contributing to redox balancing via NADH oxidation (Oliveira et al. 2023) (Fig. 1A).

As referred above, a key structural component of the EPS in S. epidermidis biofilms is the PIA, also known as poly-N-acetylglucosamine (PNAG), which plays a major role in intercellular adhesion and biofilm accumulation. Under hypoxic conditions, S. epidermidis 1457 upregulates genes involved in biofilm matrix production, notably the icaADBC operon responsible for the synthesis of PIA. This induction is associated with limited TCA cycle activity, which favours the diversion of carbon flux from glycolysis (specifically fructose-6-phosphate) through the amino sugar pathway toward UDP-sugar intermediates required for PIA biosynthesis (Somerville et al. 2002, Vuong et al. 2005) (Fig. 1A). In the PIA-defective, weak biofilm-producing strain 1457-M12, which carries a mutation in purR, a transcriptional repressor that regulates purine metabolism by repressing purine biosynthetic genes in response to intracellular purine levels, carbon is quantitatively recovered at 100% in fermentation end-products. In contrast, high biofilm-forming strains like 1457 and RP62A, grown under the same conditions, exhibit a lower carbon recovery rate ranging from 86% to 92%. The non-stoichiometric accumulation of lactate and acetate, i.e. the deviation from the expected conversion of one glucose molecule into two molecules each of lactate and acetate, in high biofilm-producing strains, suggests a redirection of carbon flux away from substrate-level phosphorylation toward alternative pathways, potentially including PIA biosynthesis and/or partial TCA cycle activity (Oliveira et al. 2023).

Upon glucose depletion, biofilms of S. epidermidis strains 1457 and RP62A sustained growth by metabolizing the extracellularly accumulated lactate, but not acetate (Oliveira et al. 2023). The glyoxylate cycle consists of two key isocitrate lyase and malate synthase. These enzymes enable cells to bypass a major limitation of the TCA cycle, which is the loss of two carbon atoms as CO₂ during the decarboxylation steps. When two-carbon compounds (e.g. acetate) are used as carbon sources, the TCA cycle activity results in carbon loss, preventing their use for net biosynthesis and cellular growth. Under these conditions, cells may survive but cannot proliferate. Therefore, under fermentative conditions, the acetate that accumulates during exponential growth of S. epidermidis strains RP62A and 1457, does not support sustained growth following glucose depletion, due to limited TCA cycle activity and the absence of a functional glyoxylate cycle (Somerville and Proctor 2009, Oliveira et al. 2023).

Glucose metabolism in S. epidermidis under anaerobic nitrate respiration

Under anaerobic conditions, when electron acceptors for the electron transport chain, such as nitrate, are available instead of oxygen, the reducing equivalents generated during glycolysis and TCA cycle activity can be reoxidized via a less efficient anaerobic respiratory chain (Fig. 2B) (Unden and Bongaerts 1997).

Nitrate has biological relevance as it is commonly found in host environments, e.g. inflamed tissues, in the micromolar range of concentrations (Schreiber et al. 2010, Winter et al. 2013, Li et al. 2022, Miller et al. 2022). Although widely employed in experimental settings, the in vitro nitrate concentrations used are often orders of magnitude higher than those observed physiologically, which facilitates detection of responses but limits its relevance. Studies show that in the presence of glucose and nitrate, electrons from menaquinone in the electron transport chain are transferred to nitrate rather than to terminal oxidases, which are functionally replaced by nitrate and nitrite reductases. This replacement occurs independently of glucose availability, as even low glucose levels induce the substitution of terminal oxidases with nitrate and nitrite reductases, as observed in S. epidermidis ATCC 12228 grown anaerobically in LB medium (Uribe-Alvarez et al. 2016) (Fig. 2B). In this strain, electron transfer to menaquinone is mediated primarily by NDH-2, Mqo1, and quinone oxidoreductase (Uribe-Alvarez et al. 2016). In biofilm cells of S. epidermidis strain 1457 grown anaerobically in TSB glucose, the expression of narG and qnor was found to be upregulated (Yao et al. 2005) and nitrate reductase was predominantly detected in the cell cultures (Martínez-García et al. 2021). In S. epidermidis strains RP62A and 1457, nitrate respiration led to the conversion of glucose-derived pyruvate into approximately similar amounts of acetate and lactate end-products, indicating an increase of acetate kinase activity and a decrease in lactate dehydrogenase activity in relation to fermentative conditions (Oliveira et al. 2023). Despite the additional ATP generated through acetate formation, this metabolic configuration is less favourable for biofilm development compared to fermentative metabolism dominated by lactate production (Schlag et al. 2007, Oliveira et al. 2023). Nitrite, the product of nitrate reduction, is relatively inefficient as an electron acceptor as it cannot efficiently couple NADH oxidation to the generation of a proton motive force. Under such conditions, redox balance is primarily maintained through lactate dehydrogenase activity, leading to even greater lactate accumulation than in purely fermentative states. This behaviour is observed when there is reduced electron acceptor utilization (Handke et al. 2008).

Amino acids

In bacteria, amino acids—which are essential for survival and colonization—can be acquired via salvage pathways, through dedicated transporters, or synthesized de novo, depending on environmental availability. Of relevance, on the skin, where glycolytic carbon sources are typically limited, skin-resident bacteria in healthy individuals utilize amino acids, such as branched-chain amino acids, proline, and alanine, derived from sweat or the degradation of structural proteins like filaggrin and collagen, as alternative non-glycolytic/gluconeogenic carbon and nitrogen sources (Kumar et al. 2019).

Although little is currently known about amino acid uptake in S. epidermidis, genomic analysis of strain RP62A has revealed the presence of putative amino acids ABC transporters and symporters, suggesting that this strain can uptake several amino acids (Gill et al. 2005, Calvo et al. 2022).

Regarding de novo biosynthesis, S. epidermidis strains harbour complete biosynthetic pathways enabling the synthesis of all standard amino acids, as inferred from genome annotations and genome-scale metabolic modelling (Gill et al. 2005, Calvo et al. 2022). In a recent study, S. epidermidis strain RP62A was cultivated in a defined glucose-based medium, with individual amino acids systematically excluded to evaluate potential auxotrophies. Except for proline, whose absence markedly reduced growth rate and final biomass yield, and valine, for which the results were inconclusive, no other amino acids were found as essential for growth, thereby confirming prototrophy under these experimental conditions (Calvo et al. 2022). Additional studies have identified conditionally auxotrophic phenotypes in catheter-isolated S. epidermidis strains. For example, stable small-colony variants (SCVs) were found to exhibit glycine auxotrophy due to a frameshift mutation in the alanine–glyoxylate aminotransferase gene, disrupting endogenous glycine biosynthesis and rendering growth dependent on external glycine (Liu et al. 2021). Similarly, in S. epidermidis ATCC 12228, deletion of both alanine racemase genes (alr1 and alr2) led to a D-alanine auxotrophic phenotype, requiring its exogenous supplementation for survival (Dodds et al. 2020).

S. epidermidis strain 19 N, grown aerobically under planktonic conditions in TSB at healthy skin pH (∼5.5), exhibited high intracellular accumulation of glutamate and increased production of the proteins GltB and GltD, which synthesize glutamate from the TCA cycle intermediate 2-oxoglutarate. The authors proposed that glutamate not only serves as a central metabolic node, linking carbon and nitrogen metabolism, but is also involved in resistance to several stresses, including acid stress (Gonçalves et al. 2022). The same role was attributed to arginine and the Arginine Deiminase Pathway (ADI) pathway in maturing biofilms. The importance of this pathway was demonstrated by Lindgreen and coworkers (Lindgren et al. 2014), who showed that deletion of both ADI enzymes (arcA1 and arcA2) in S. epidermidis 1457 resulted in a significant loss of viability in mature biofilms under acidic conditions, despite the presence of extracellular arginine. The authors suggest that ammonia production via the ADI pathway is essential for pH regulation and biofilm integrity during late stages of development.

While ammonia, a by-product of amino acid catabolism, contributes to pH regulation, the potential role of carbamoyl-phosphate generated by the ADI pathway in ATP production and biofilm viability was not investigated.

When S. epidermidis strain 19 N was grown under aerobic planktonic conditions, a shift in medium pH from 5.5 (skin pH) to 7.4 (blood pH) resulted in high intracellular accumulation of BCAAs, aspartate, asparagine, phenylalanine, and tyrosine. These findings suggest a dual role for these amino supporting anabolic processes such as protein synthesis, while also serving as substrates for energy production through their respective catabolic pathway. Furthermore, the expression of proteins involved in proline biosynthesis (ProC) and catabolism (PutA, RocA) under the same conditions suggest a role for proline in adaptation to the bloodstream environment (Gonçalves et al. 2022).

A comparative transcriptomics of S. epidermidis strain 9142 biofilm-released cells (BRC) incubated with whole human blood versus BRC incubated with TSB showed enrichment of genes encoding amino acid biosynthetic and metabolic pathways, including those for BCAAs (França et al. 2016b), suggesting an important role of amino acids during S. epidermidis interaction with blood.

Interestingly, S. epidermidis 1457 cells grown aerobically in TSB exhibit intracellular accumulation of BCAAs when the TCA cycle is inactivated. Under these conditions, pyruvate is thought to be redirected toward mixed-acid fermentation and the acetolactate synthase pathway, generating key precursors for BCAA biosynthesis, such as oxaloacetate and α-ketoisovalerate (Sadykov et al. 2008).

Lipids and fatty acids

In a skin metatranscriptomics study in which samples were collected from multiple body sites, S. epidermidis was prevalent across the skin but presented higher transcriptional activity in sebaceous sites like scalp and cheek compared with non-sebaceous sites, including the toe web, volar forearm and antecubital fossae (Chia et al. 2025). This observation could suggest that S. epidermidis utilizes host lipids or their derived building blocks, fatty acids, for growth. However, unlike many bacteria that exploit fatty acids as primary carbon and energy sources, S. epidermidis shows limited capacity for fatty acid uptake, with metabolism oriented toward detoxification and selective membrane remodelling. This may be due to the inability of S. epidermidis to utilize fatty acids as sole carbon or energy sources, resulting from the absence of a glyoxylate cycle—a metabolic pathway required for growth on two-carbon compounds (Chamberlain and Brueggemann 1997, Chamberlain 1999).

In one lipidomic study of a S. epidermidis skin isolate, researchers identified functional homologs involved in fatty acid activation and incorporation and observed pronounced shifts in membrane composition during the transition from exponential growth to nutrient-starved stationary phase. During active growth, S. epidermidis displayed a glycerolipid profile comprising phosphatidylglycerol (PG), lysyl-PG, diacylglycerol (absent in S. aureus), diglucosyl-diacylglycerol, and lysyl-diacylglycerol. Upon nutrient depletion, there was a marked reduction in nitrogen-containing lipids, likely reflecting halted anabolic processes, accompanied by an accumulation of free fatty acids (C12–C22). This pattern suggests that fatty acid synthesis continued, but their incorporation into complex lipids was impaired. In response, S. epidermidis markedly increased cardiolipin levels and produced acyl-phosphatidylglycerol—adaptations that were not observed in S. aureus (Luo et al. 2018). These changes mirror starvation responses in organisms such as E. coli and Bacillus subtilis, where cardiolipin supports membrane curvature, stress adaptation, and respiratory complex stabilization (Romantsov et al. 2009).

One important aspect of S. epidermidis lipid metabolism is the production of the fatty acid modifying enzyme (FAME). This secreted enzyme catalyses the esterification of antimicrobial host fatty acids- such as sapienic and palmitoleic acids- with cholesterol or other alcohols, thereby rendering the fatty acids non-toxic to bacteria. FAME is a salt-tolerant protein that exhibits optimal activity under acidic conditions, consistent with skin pH, and is present in over 88% of clinical S. epidermidis isolates, highlighting its importance for cutaneous survival (Chamberlain and Brueggemann 1997, Chamberlain 1999). The recent identification of a similar activity in S. aureus by lipase Lip2, which was shown to detoxify antimicrobial fatty acids through esterification with cholesterol and to enhance in vivo skin colonization in a mouse model, suggests that fatty acid esterification may represent a broader staphylococcal strategy for host adaptation (Kengmo Tchoupa et al. 2024).

A study on S. epidermidis strain ATCC 12228 (Tiwari et al. 2020) revealed marked metabolic plasticity in response to environmental alterations. Under standard laboratory conditions, the membrane was found to contain mainly branched-chain fatty acids (BCFAs) (about two-thirds of total fatty acids) which contribute to fluidity and stability, similar to what was observed in other coagulase-negative staphylococci. Fatty acid composition shifted with environmental cation-supplemented Mueller–Hinton broth increased BCFA levels, while serum-supplemented media led to incorporation of host-derived straight-chain unsaturated fatty acids. These findings suggest that because S. epidermidis strains can incorporate host lipids and bypass endogenous fatty acid synthesis, targeting the FAS-II pathway may be ineffective in vivo. The susceptibility to antimicrobial-innate derived fatty acids, like sapienic acid, indicates that detoxification mechanisms such as FAME are likely more critical for resisting host defences than membrane composition changes (Tiwari et al. 2020).

Complementing these findings, another study showed that acidic conditions, mimicking the skin’s natural pH, induce the expression of lipid-hydrolyzing enzymes in S. epidermidis 19 N, including lipases and esterases. These enzymes release fatty acids from host phospholipids and triglycerides, which can then be incorporated into membranes, or potentially influence host responses. This pH-driven adaptation underscores the bacterium’s ability to thrive in the lipid-rich, acidic environment of human skin. In contrast, at blood pH, fatty acid-related membrane synthesis is reduced, suggesting a downregulation of lipid metabolism in systemic contexts (Gonçalves et al. 2022).

Taken together, S. epidermidis exhibits a non-canonical pattern of lipid interaction, balancing minimal uptake with detoxification (via FAME), selective membrane incorporation, and regulatory modulation, which contributes to its role as a skin commensal.

Transcriptional control of S. epidermidis metabolism

This section addresses the regulatory networks governing metabolic adaptations in S. epidermidis. It examines major transcriptional regulators (i.e. SaeRS, GdpS, SrrAB, IcaR/Sigma B, CcpA, CodY) and post-transcriptional regulators (i.e. sRNAs icaZ and RsaE) that coordinate aerobic and anaerobic respiration, fermentative pathways, and the biosynthesis of PIA, a critical structural component in S. epidermidis biofilms. These regulatory systems facilitate the bacterium’s ability to sense and respond to fluctuations in nutrient availability, oxygen tension, pH, and temperature (Fig. 3). Herein, genes are referred to by the locus tags reported in the original studies, annotations that may differ from that of the current chosen genome NCBI reannotation.

SaeRS

S. epidermidis possesses a two-component transcriptional regulator that shares high degree of similarity with the S. aureus SaeR. It consists of an exoprotein response regulator and sensor histidine kinase, which responds to environmental conditions such elevated salt levels, low pH, glucose, and sub-inhibitory concentrations of antibiotics (Norvick and Jiang 2003, Handke et al. 2008).

Previous transcriptomic analysis of S. epidermidis 1457 and its saeR deletion mutant showed that SaeR promotes expression of genes involved in anaerobic metabolism, including enzymes for C₄-dicarboxylate transport, NADH oxidation, and anaerobic ribonucleotide reduction, while repressing genes in pyruvate fermentation. In contrast, genes for amino acid biosynthesis, particularly histidine and arginine, were upregulated in the mutant (Handke et al. 2008). Based on this data, SaeR appears to influence the transition between aerobic and anaerobic growth in S. epidermidis. This has been interpreted to suggest that SaeR contributes to metabolic adaptation under changing oxygen conditions, although the precise mechanisms and broader physiological implications remain to be fully defined.

When cultured under anaerobic conditions in medium supplemented with nitrate the saeR mutant strain of S. epidermidis 1457 exhibited a reduced growth rate, which led to increased lactate accumulation and slight enhancement of biofilm production (Handke et al. 2008). These findings indicate a metabolic shift toward lactate fermentation resulting from impaired nitrate utilization as an electron acceptor and suggest a role for SaeR in facilitating anaerobic nitrate respiration (Fig. 2B). Redox-related genes, including the rex repressor, trxA (thioredoxin), and trxB (thioredoxin reductase), were also upregulated in the saeR mutant, indicating disrupted redox homeostasis characterized by an altered NAD⁺/NADH ratio and associated compensatory metabolic adjustments. However, S. epidermidis saeR mutant did not exhibited reduced virulence in a murine foreign-body infection model, despite showing diminished recruitment of polymorphonuclear neutrophils at two days post-infection, suggesting an impact on early immune response dynamics (Handke et al. 2008).

Lou and colleagues (Lou et al. 2014) performed a comparative proteomic analysis of S. epidermidis 1457 wild-type and saeRS mutant strains grown under aerobic conditions and identified 55 proteins with significantly altered abundance. Figure 1 contains metabolic pathways activated and inhibited by transcriptional regulators, including SaeR, based on our review of the available data. Among the altered proteins, in the saeRS mutant multiple enzymes of glycolysis (e.g. fructose bisphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase) and the TCA cycle (e.g. succinyl-CoA synthase, isocitrate dehydrogenase) had decreased expression and phosphotransacetylase (Pta) showed increased abundance. Comparative qRT-PCR analysis of the corresponding genes revealed a similar pattern of expression. The authors interpreted this pattern as indicating impaired glucose utilization in the absence of SaeRS and a diversion of acetyl-CoA toward acetate production via Pta. However the lack of direct metabolite or flux measurements limits the conclusions, leaving unresolved how acetyl-CoA is supplied to Pta despite reduce abundance of glycolysis and TCA cycle enzymes.

GdpS

S. epidermidis GdpS is a GGDEF domain-containing protein that is similar to those found in di-guanylate cyclases that synthesise cyclic-di-GMP (c-di-GMP), a universal bacterial second messenger involved in the transition from the planktonic to biofilm state (Römling et al. 2013). In strain RP62A, GdpS contributes to biofilm formation via transcriptional activation of the ica genes responsible for the synthesis of PIA (Zhu et al. 2017) (Fig. 1C). Furthermore, the gdpS mutant strain treated with glycerol and exposed to low temperature during cryopreservation enters a viable but non-culturable (VBNC) state and exhibits extensive transcriptional changes, particularly in pathways related to glycerol metabolism and nitrate reduction. Specifically, mutation of gdpS results in activation of the glpFKD operon and glpT, boosting glycerol metabolism, as well as upregulation of the narGHJI, narT, and nirBD genes, which promote nitrate and nitrite reduction, indicating a metabolic shift toward anaerobic respiration. This coordinated metabolic stress response of the gdpS mutant suggests that the bacterium may utilize glycerol as a carbon source and nitrate as an electron acceptor under low-oxygen, low temperature and nutrient-limited conditions (Zhu et al. 2022).

SrrAB

The Staphylococcal Respiratory Response SrrAB two-component transcriptional regulatory system, originally identified in S. aureus (Yarwood et al. 2001), functions as an oxygen sensor that enables Staphylococcus species to adapt to oxygen-limiting conditions. In S. epidermidis 1457, the srrAB expression is upregulated under reduced oxygen conditions, indicating its role in the regulatory response during the transition from aerobic to microaerobic environments. Furthermore, under reduced oxygen conditions, deletion of srrA alters the expression of ∼4.5 times more genes than under aerobic conditions (Wu et al. 2015). Independently of the oxygen content in the bacterial culture, in strain 1457 the deletion of srrA leads to downregulation of genes involved in aerobic respiration, particularly qoxBACD and ctaA, as well as genes related to anaerobic respiratory and fermentative metabolisms, including pflBA (formate acetyltransferase), nrdD (anaerobic ribonucleoside triphosphate reductase), serp0257 (alcohol dehydrogenase), serp2257 (acetoin reductase), and serp2381 (NADH: flavin oxidoreductase). Phosphorylated SrrA binds directly to the promoter regions of both the qoxBACD and pflBA operons, confirming its direct regulatory role (Wu et al. 2015). It is hypothesized that SrrAB supports aerobic growth by upregulating genes encoding components of the electron transport chain (qoxBACD, ctaA), while under microaerobic conditions it shifts to activating fermentative metabolism and DNA synthesis pathways (e.g. pflBA, nrdD) (Figs. 1B,C and 2A). This dynamic regulatory adjustment results in an efficient change of S. epidermidis metabolism according to oxygen availability (Wu et al. 2015).

One of the most notable findings is the strong effect of SrrAB on biofilm formation. Deletion of srrA in strain 1457 leads to significant downregulation of the ica genes encoding the PIA synthesis machinery, and results in a marked reduction in biofilm production (Wu et al. 2015). Initial adherence to surfaces is also impaired in the mutant strain, indicating that SrrAB is also essential for the early stages of biofilm development (Wu et al. 2015).

IcaR and Sigma B

Sigma B is a transcriptional regulator that responds to general stress and is indirectly modulated by oxygen levels. Its activity increases under anaerobic conditions in S. epidermidis strain 1457, where it represses the transcription of icaR (intercellular adhesion regulator), a negative regulator of the icaADBC operon (Cotter et al. 2009b). The icaR gene is located immediately upstream of icaADBC and is transcribed in the opposite direction. By repressing icaR, SigmaB indirectly activates icaADBC expression, thereby promoting biofilm formation (Fig. 1C). Consequently, low oxygen levels enhance biofilm production through this regulatory pathway (Conlon et al. 2002, Jeng et al. 2008, Cotter et al. 2009b). Interestingly, Sigma B from S. epidermidis strain Tü3298, which lacks the icaABCD operon, had no effect on the heterologous formation of a S. carnosus biofilm (Kies et al. 2001).

TcaR (teicoplanin-associated locus regulator) regulator, first identified in S. aureus, was also found to repress the icaADBC operon in strains 1457 and CSF41498 (the later isolated from cerebrospinal fluid, obtained from a neurosurgical device-related infection, biofilm^+^ and ica^+^). The authors showed that when icaR is repressed, TcaR functions as the primary repressor in these strains (Hoang et al. 2019).

CcpA and SarA

CcpA (catabolite control protein A) is a global transcriptional regulator belonging to the GalR-LacI family, which mediates carbon catabolite repression (CCR) across a wide range of Gram-positive bacteria. CCR enables these organisms to preferentially utilize energetically favourable carbon sources, such as glucose, by repressing the transcription of genes involved in the metabolism of less-preferred substrates (Carvalho et al. 2011).

In S. epidermidis 1457, CcpA represses key TCA cycle genes, including citZ and acnA (Fig. 1D), however residual TCA cycle activity remains detectable even under CcpA-mediated repression. Loss of ccpA leads to derepression of TCA activity during aerobic growth in glucose (Sadykov et al. 2010, 2011). The ccpA mutant forms less biofilm under static conditions. While ccpA deletion only modestly reduces icaADBC transcription in the wild type, the effect is markedly stronger in a TCA-deficient background (ΔacnA), suggesting that CcpA controls PIA synthesis indirectly through TCA-derived metabolic signals rather than by direct regulation of icaADBC (Sadykov et al. 2010, 2011).

A ¹H-NMR-based metabolomics analysis of S. epidermidis 1457 revealed that disruption of the TCA cycle, induced by ethanol stress, iron limitation, or by deletion of the aconitase gene, results in the accumulation of glycolytic intermediates (e.g. glucose-6-phosphate), precursors for amino sugar biosynthesis (GlcN6P, UDP-GlcNAc, UDP-ManNAc), mixed-acid fermentation products (lactic acid, acetaldehyde, acetyl-phosphate, acetic acid), and pentose phosphate pathway intermediates (ribose), along with a decrease in the levels of asparagine, glutamate, and glutamine (Sadykov et al. 2010). Any of the accumulated metabolic intermediates may serve as signalling molecules contributing to the observed increase in PIA synthesis; however, their specific roles remain to be experimentally validated. Furthermore, chemical inhibition of aconitase using fluorocitrate has been shown to enhance PIA production. Notably, in S. epidermidis 1457, TCA cycle-dependent regulation of the icaADBC operon and PIA synthesis occurs independently of IcaR and Sigma B (Sadykov et al. 2008).

PIA production is also dependent on the transcriptional regulator SarA (staphylococcal accessory regulator A) that directly activates the ica locus, as shown in S. epidermidis clinical O-47 isolated from orthopaedic implant infection (biofilm^+^, ica^+^, producer of PIA and protein matrix,) and in CH845 isolated from prosthetic joint infection (biofilm^+^ and ica^+^) (Fig. 1B). In the absence of SarA, both PIA/PNAG synthesis and biofilm formation are reduced. However, given that SarA regulates multiple virulence-associated genes and that TCA cycle-derived signals modulate icaADBC expression independently of IcaR and stress-responsive sigma B factor, it is likely that at least one additional, yet unidentified, regulatory factor mediates the response to TCA cycle-associated metabolic signals (Tormo et al. 2005).

CodY and Agr

CodY is a transcriptional regulator that responds to nutrient availability, particularly the presence of amino acids. It primarily acts as repressor of genes involved in amino acid metabolism (uptake and biosynthesis), especially in nutrient-rich conditions (Batte et al. 2018, Kaiser et al. 2018, Wu et al. 2022, Gao et al. 2023, Alqahtani et al. 2024).

In S. epidermidis strain 1457, viable but non-culturable (VBNC) cells accumulate in biofilms and planktonic cultures grown in the presence of excess glucose, possibly because of acidic byproducts generated during glucose metabolism. VBNC cells show increased expression of codY and pdhA (pyruvate dehydrogenase E1 alpha subunit of the pyruvate dehydrogenase complex) compared to non-inducing conditions (e.g. cultures supplemented with MgCl₂), suggesting that these genes may contribute to stress adaptation (Gaio et al. 2021). Although the signals triggering their activation remain unclear, pdhA likely contributes to stress resistance by facilitating energy production through linking glycolysis to the TCA cycle and thereby promoting metabolic flexibility. Concurrently, codY may help conserve cellular resources by repressing non-essential pathways during stress conditions. CodY deletion leads to reduced viability of both biofilms and VBNC cells, and stimulates cytokine production in human macrophages (Nathalie Lopes et al. 2024).

The accessory gene regulatory (Agr) system is a well-characterized quorum-sensing mechanism in staphylococci (Olson et al. 2014), whose activity is linked to the metabolic state of the cells in response to increased cell density.

In S. epidermidis clinical strain 567 (wildtype from catheter-associated urinary tract infection, protein-based biofilm, ica^+^), deletion of the agr system lead to downregulation of CodY, resulting in a upshift of amino acid biosynthesis and uptake pathways (Batzilla et al. 2006). Therefore, Agr plays a role not only in coordinating biofilm formation and virulence, as concluded from indirect increase in biofilm formation upon agr deletion in strain 1457, but also in fine-tuning metabolic processes through its regulation of CodY (Vuong et al. 2003, 2004b, Batzilla et al. 2006). Furthermore, S. epidermidis 1457 Agr quorum-sensing regulon was shown to coordinate a shift in cellular metabolism that occurs at high cell density, promoting survival under nutrient-limiting conditions as the cells enter the stationary phase (Yao et al. 2006).

Small regulatory RNAs: IcaZ and RsaE

The expression of the icaADBC operon is regulated by transcriptional mechanisms that are responsive to environmental signals and the metabolic state of the cell (Fig. 1C). In addition, recent work has revealed a post-transcriptional regulatory layer mediated by small regulatory RNAs (sRNAs), which are non-coding RNA molecules involved in gene regulation of bacterial physiology, fine-tuning gene expression in response to changing environmental conditions.

In S. epidermidis strain O-47, the sRNA IcaZ, identified by Lerch et al. 2019, is a ∼400 nucleotide long noncoding RNA transcribed from a locus immediately downstream of the icaR gene. IcaZ regulates biofilm formation by specifically binding to the 5' untranslated region (UTR) of the icaR mRNA. This interaction inhibits translation of IcaR, effectively reducing the intracellular levels of this repressor protein. As a result, repression of icaADBC is relieved, enabling higher transcription of the operon and enhanced production of PIA. Importantly, strains of S. epidermidis lacking IcaZ show markedly reduced biofilm formation, confirming the functional relevance of this RNA in promoting biofilm development.

RsaE is also a small non-coding RNA (sRNA) conserved across low-GC Gram positive bacteria including S. epidermidis, yet its functional role exhibits remarkable divergence between species.

An extensive study of Schoenfelder and colleagues (Schoenfelder et al. 2019) reported that in S. epidermidis RsaE influences the composition of the extracellular matrix within biofilms. It promotes a shift toward PIA-dominated biofilm formation, even in strains that typically produce protein-based or low-PIA biofilms. This includes two blood culture isolates (strains PS2 and PS10) and two clinical isolates (strains 567 and O-47), all of which are biofilm*^+^* and ica^+^, but vary in matrix composition. RsaE exerts its effect by targeting multiple regulatory it represses icaR and sucCD, the latter encoding succinyl-CoA synthetase, a TCA cycle’s enzyme. By downregulating sucCD, RsaE diverts carbon flux away from energy respiration and toward the synthesis of PIA precursors, thereby facilitating PIA matrix accumulation (see also section Glucose metabolism in S. epidermidis under fermentative conditions).

RsaE in S. epidermidis exists in two a full-length transcript and a 5′-truncated variant, each regulating distinct targets. The full-length form specifically represses lrgA, which encodes an antiholin that inhibits autolysis. By downregulating lrgA, RsaE promotes programmed cell lysis in certain biofilm subpopulations, resulting in the release of extracellular DNA (eDNA), which is a key structural element that provides biofilm integrity. This regulatory function introduces different population levels in which metabolically adapted, and matrix-contributing subpopulations (lysis-prone cells) coexist, the latter sacrificing for the first (Schoenfelder et al. 2019).

Adaptation strategies of S. epidermidis to host environmental challenges

In S. epidermidis, pathogen-associated molecular patterns (PAMPs) such as lipoteichoic acid and peptidoglycan are primarily recognized by Toll-like receptor 2 (TLR2), a major sensor of Gram-positive bacteria. This interaction initiates a cascade of immune responses, including phagocytosis, the production of pro-inflammatory cytokines, the release of antimicrobial peptides, and the activation of the adaptive immune system (Michael Otto 2009, Wanke et al. 2011, Fu and Harrison 2021, Burke et al. 2024). Among host defences, antimicrobial mechanisms include the activities of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and inducible nitric oxide synthase (iNOS), which generate superoxide and nitric oxide, respectively. These reactive molecules give rise to highly reactive species known as reactive oxygen species (ROS) and reactive nitrogen species (RNS), contributing to the elimination of invading pathogens.

As both a skin commensal and opportunistic pathogen, S. epidermidis must withstand not only host immune effector mechanisms but also environmental fluctuations in oxygen concentration, temperature, pH, and nutrient availability (Fig. 3). To achieve this, S. epidermidis employs a variety of strategies, including the production of secreted molecules and enzymes that modulate host responses, facilitate survival under stress, and promote biofilm formation.

Among the secreted molecules, S. epidermidis produces phenol-soluble modulins (PSMs), which are small amphipathic peptides that can modulate host immune responses by recruiting and activating neutrophils, promoting biofilm structuring, and in some cases exhibiting cytolytic activity against host cells. S. epidermidis PSMs include the δ-toxin–like PSMδ and the β-type PSMβ peptides, whose Agr-regulated expression is highest under slow-growth conditions and nutrient limitation. The amphipathic, surfactant-like properties of PSMs destabilize the biofilm by loosening its surface and facilitate the exit of actively growing daughter cells, allowing them to colonize new niches (Vuong et al. 2004a, Otto 2014).

In addition to PSMs, S. epidermidis employs other extracellular polymers such as poly-γ-dl- glutamic acid (PGA) to enhance survival under environmental and immune pressures. PGA, encoded by the cap operon, is also responsive to environmental and metabolic pressures and contributes to biofilm formation. PGA production increases during oxidative stress, iron limitation and reduced TCA cycle activity, although the underlying mechanism remains undefined. PGA accumulation enhances resistance to antimicrobial peptides and impairs phagocytosis, thereby contributing to persistence in nutrient-poor or inflammatory environments (Kocianova et al. 2005, Fey and Olson 2010).

Other secreted enzymes that facilitate nutrient acquisition and biofilm maturation include lipases that act on skin lipids, proteases such as SepA that modulate surface proteins, and extracellular nucleases. Their production is regulated by global transcriptional regulators such as SigB and SarA, which respond to nutrient limitation, osmotic stress, and other environmental challenges (Rosenstein and Götz 2000, Kies et al. 2001, Knobloch et al. 2001, Lauderdale et al. 2009, Christner et al. 2012, Paharik et al. 2017, Martínez-García et al. 2018).

Innate immune effectors

Multiple studies have demonstrated that S. epidermidis elicits oxidative and nitrosative bursts. Specifically, clinical strains of S. epidermidis from neonatal blood cultures of both preterm and term infants stimulate neutrophils and production of superoxide, as assessed by flow cytometry. Interestingly, preterm infants exhibited a significantly attenuated ROS response compared to term infants, consistent with age- and maturity-dependent differences in innate immune function (Björkqvist et al. 2004).

Extending these observations, both planktonic cells and biofilms of S. epidermidis RP62A were reported to activate human neutrophils, inducing rapid superoxide production, with biofilm-rich variant strains eliciting significantly higher levels (Heinzelmann et al. 1997). Further supporting this, studies on opsonized S. epidermidis biofilms revealed that the presence of human complement and antibodies promote neutrophils´ ROS release (Brescó et al. 2017).

In addition to neutrophils, epithelial cells of the human upper airway contribute to host defence against S. epidermidis. Sinonasal epithelial cells were shown to produce NO upon exposure to several strains of S. epidermidis, (including RP62A, 12 228, 1457), a response proposed to be mediated by bitter taste receptors (T2Rs) (Carey et al. 2016).

Complementing these findings, bacterial components such as short-chain lipoteichoic acid (LTA) from S. epidermidis have been demonstrated to induce significant inducible nitric oxide synthase (iNOS) expression and NO production, alongside elevated levels of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α, in both macrophage cell lines and primary human nasal epithelial cells (Jones et al. 2005).

Moreover, the S. epidermidis biofilm matrix has been implicated in modulating macrophage responses. Biofilm´s EPS components were found to stimulate NO release in murine peritoneal macrophages, indicating that biofilm matrix components themselves can act as immune stimuli (Stout et al. 1994).

Taken together, these studies demonstrate that ROS burst responses to S. epidermidis predominantly occur in neutrophils, especially in response to biofilm forms and slime-producing strains, while NO production is largely driven by macrophages and epithelial cells in response to specific bacterial components such as LTA, EPS, and secreted factors (Burke et al. 2024) (Table 3).

S. epidermidis oxidative and nitrosative defences

Given the potent antimicrobial properties of ROS and RNS—which inflict damage on DNA, lipids, and proteins, and disrupt essential cellular functions such as enzyme activity, ion transport, and gene regulation (Carvalho et al. 2022, Kondengadan and Wang 2024, Okda et al. 2025)—it is relevant to understand how S. epidermidis withstands oxidative and nitrosative stresses. This resistance is sustained by responsive genes that encode ROS, NO and S-nitrosothiols scavengers, and repairing enzymes. Additional enzymes involved in regenerating reduced pyridine nucleotides, repairing DNA, and regulating iron homeostasis further contribute to the bacterium’s ability to mitigate stress-induced damage. An overview of these oxidative and nitrosative defence systems characterized in S. epidermidis is summarized in Fig. 4.

Despite these protective mechanisms, oxidative and nitrosative bursts still disrupt key metabolic processes. A transcriptomic study of S. epidermidis 1457 exposed to hydrogen peroxide (Zhao et al. 2025) showed the downregulation of genes involved in both aerobic respiration (quinol oxidases qoxBACD and ctaA) and genes of anaerobic fermentation pathways (pyruvate formate-lyase enzymes pflBA, anaerobic ribonucleotide reductase components nrdDG), and thiamine (vitamin B₁) biosynthesis protein, leading to reduced energy production and increased ROS from uncontrolled respiratory flux. Furthermore, the build-up of ROS causes oxidative damage to Fe-S cluster-containing enzymes critical for central metabolism, disturbs transition metal ion homeostasis (affecting cofactors like Fe²⁺, Mn²⁺, and haem), collapses intracellular redox balance, and severely represses detoxification mechanisms by reducing expression of ROS-scavenging genes such as katA (catalase), ahpC (alkyl hydroperoxide reductase), scdA (Fe-S cluster repair protein), and thioredoxins (serp0483), which altogether destabilizes cellular metabolism. To partially counteract this oxidative injury, the bacterium upregulates stress-responsive and redox-balancing pathways including quinone oxidoreductases (mqo-3, increased over 50-fold), one-carbon metabolism enzyme fhs, thiamine biosynthesis genes, and several types of oxidoreductases, aiming to restore electron flow, sustain NADH/NAD⁺ balance, and maintain minimal metabolic function for survival under oxidative pressure (Spahich et al. 2016, Zhao et al. 2025).

The effects of NO on S. epidermidis, as well as the bacterial responses to RNS, remain poorly characterized with few studies available to date. Our group demonstrated by transcriptional analysis for S. epidermidis strains 1457 and RP62A that NO induces the expression of ica A, which is directly involved in PIA production, along with genes encoding proteins in the amino sugar pathway (glmM and glmU) that connect glycolysis to PIA synthesis. Metabolomic profiling further revealed that NO resistance is achieved through upregulation of glycolysis and increased lactate dehydrogenase activity, accompanied by suppression of metabolic pathways at the pyruvate node and TCA cycle (Oliveira et al. 2023).

The ability of S. epidermidis to form biofilms adds another layer of protection from host-derived antimicrobial stresses (e.g. oxidative/nitrosative stress), with the biofilm extracellular matrix serving as a physical barrier to phagocytes (Vuong et al. 2004c, Cerca et al. 2006, Kristian et al. 2008, Cheung et al. 2010, Aarag Fredheim et al. 2011, Schommer et al. 2011, Thurlow et al. 2011, Spiliopoulou et al. 2012, Weißelberg et al. 2024, Evans et al. 2025).

Some of the systems shown in Fig. 4 protect S. epidermidis biofilm cells from oxidative stress and contribute to biofilm stability. For example, catalase decomposes hydrogen peroxide (Liu et al. 2013, Olwal et al. 2019); alkyl hydroperoxide reductase AhpC reduces organic hydroperoxides (Montanhero Cabrera et al. 2023); the ferric uptake regulator Fur controls iron homeostasis and limits oxidative damage (Oliveira et al. 2021, 2022); the chaperonin GroEL assists in proper protein folding under stress (Dapunt et al. 2016); SrrAB regulates the stress response under low oxygen (Wu et al. 2015); Iron-regulated haem transport system Hts and ferric hydroxamate uptake FhuC ensure iron availability while limiting harmful radicals (Oliveira et al. 2022, Montanhero Cabrera et al. 2023); and caseinolytic protease P ClpP degrades misfolded or damaged proteins, maintaining cellular integrity (Wang et al. 2007).

Like some other bacteria, S. epidermidis produces endogenous NO through the nitric oxide synthase seNOS in a tightly regulated process that generates low levels of NO, which support beneficial functions such as signalling, protection against oxidative stress, and influence biofilm development through a complex regulatory network (Zhao et al. 2025). Although the NO detoxifying enzyme flavohaemoglobin is also present in S. epidermidis, it became active only when the intracellular levels of NO raise (Singh et al. 2023). Furthermore, the low levels of NO produced by seNOS are considered to promote biofilm dispersal helping bacteria transition from a sessile (attached) biofilm state back to a planktonic (free-floating) lifestyle, which is for spreading and colonization (Wang et al. 2022).

Staphylococcus epidermidis environmental adaptation

During infection or upon colonization of medical devices, S. epidermidis may be exposed to microenvironments that diverge from its optimal growth conditions. Furthermore, S. epidermidis occupies niches with variable oxygen concentrations, and adaptation involves shifts from aerobic respiration, driven by quinol oxidases, to nitrate respiration via nitrate reductase, or fermentation in low-oxygen or anaerobic conditions (Uribe-Alvarez et al. 2016). Nitrate and nitrite inhibit biofilm formation, likely due to the nitrosative stress mediated by NO, which is produced through the activity of nitrite reductase (NirBD) (Fig. 2B). This effect is associated with repression of the icaADBC operon for PIA biosynthesis (Schlag et al. 2007, Oliveira et al. 2023). Interestingly, implant surfaces coated with materials that release NO are showing success in preventing biofilm formation (Nablo et al. 2005, Xu et al. 2017, Li et al. 2020, Gondil et al. 2025). Under microaerobic conditions, inhibition of nitrate reductase by methylamine led to an additional reduction in biofilm formation, possibly due to the forced reliance on aerobic respiration (Uribe-Alvarez et al. 2016). This transition that directly promotes biofilm formation and enhances persistence in hypoxic environments involves metabolic changes that have been discussed in detail in section Transport and metabolism in S. epidermidis.

S. epidermidis grows optimal at temperature and pH closely matching those of human skin, and can utilize a variety of carbon sources, with glucose serving as a preferred substrate. The response of S. epidermidis ATCC 12228 to temperature variations was investigated in a recent transcriptomic study examining gene expression following a temperature shift from 37°C to 45°C (Benjamin et al. 2024). It was observed differential expression in ∼16% of the genes, including classical heat shock genes such as dnaK, groESL, clpC, clpP, and clpB. While S. epidermidis exhibits the typical Gram-positive heat shock response mediated by HrcA and CtsR, it may rely on an alternative stress response system of the sigma-70 family that operates independently of the canonical sigma B regulon (Benjamin et al. 2024).

In the same study, the cellular transcriptional responses to physiologically relevant glucose concentrations were also explored (2–5 mM). By subjecting S. epidermidis to either acute glucose spikes or sustained glucose levels (2–50 mM), the glucose spikes resulted in the downregulation of genes involved in the metabolism of secondary carbon sources, including those required for lactose metabolism, ribose transport, fructose utilization, proline catabolism, the glyoxalase pathway, the succinate dehydrogenase complex, and ethanol degradation. In contrast, sustained glucose conditions induced several essential glycolytic dha operon encoding proteins involved in the phosphorylation of dihydroxyacetone (DHA) that is a key step in glycerol metabolism; gluconeogenesis-associated genes; and genes involved in the tricarboxylic acid (TCA) cycle. These findings indicate that S. epidermidis responds to glucose spikes with a transcriptional pattern of carbon catabolite repression (Benjamin et al. 2024).

S. epidermidis metabolic and proteomic profiles are also modulated by environmental pH variations encountered during the transition from the acidic skin surface to the neutral-to-alkaline conditions of blood. In the slightly acidic skin niche (around pH 5.5), the bacterium activates oxidative stress response and biosynthesis pathways involving peptidoglycan, lipoteichoic acids, and betaine, which are critical for maintaining cell wall integrity and osmotic balance. The shift to blood pH induces reduction of intracellular betaine concentrations, and significant alterations in metabolites and proteins involved in redox balance and homeostatic regulation (Gonçalves et al. 2022).

The sigma B factor also contributes to tolerance of skin swab isolates to stress created by physico-chemical disinfectors, such as 50°C, 5 mM NaOCl or 50 μM H2O2 (Olwal et al. 2019) and contributes to disintegration of biofilms of strain 1457 under glucose limited conditions (Jäger et al. 2009).

Altogether data show that S. epidermidis adapts to fluctuating oxygen, nitrogen, glucose, temperature, and pH by coordinating metabolic shifts, stress responses, and icaADBC-regulated biofilm formation. These integrated responses allow it to maintain energy homeostasis and persist under conditions mimicking skin, blood, and medical-device environments.

Metabolic divergences between S. epidermidis and S. aureus

Much of our current understanding of S. epidermidis metabolism and its interplay with virulence has been driven by metabolic frameworks originally established for S. aureus. Consequently, interpretations of S. epidermidis observations often refer back to S. aureus data for comparison and context (Somerville and Proctor 2009, Sadykov et al. 2011, Calvo et al. 2022, Leonidou et al. 2025). Despite being closely related species that inhabit overlapping niches on the human body, S. epidermidis and S. aureus exhibit significant differences in metabolism, nutrient acquisition strategies, and regulatory responses, which reflect their divergent ecological niches. In this section we will emphasize those differences in sugar transport (section Sugar transport), central carbon metabolism (section Central carbon metabolism), electron transport chain (section Electron transport chain—terminal oxidases) and metabolic regulation (section Metabolic regulation).

Sugar transport

One key distinction between S. epidermidis and S. aureus lies in their sugar transport and utilization systems. S. epidermidis lacks several PTS sugar transporters, particularly those for mannitol, sorbitol, and pentitol, all of which are encoded in the S. aureus genome (Gill et al. 2005). This metabolic disparity is further amplified by the broader repertoire of glucose transporters in S. aureus, which harbours three PTS glucose systems (GlcA, GlcB, and GlcC), an ABC-type transporter (GlcU), and a glucose-6-phosphate antiporter (UhpT) (Vitko et al. 2016, Reed et al. 2018, Stephens and Richardson 2022). Among these, GlcA and GlcC appear to be exclusive to S. aureus, while GlcB, GlcU, and UhpT are more conserved across coagulase-negative staphylococci. This enhanced capacity for carbohydrate import likely contributes to S. aureus’s ability to thrive in nutrient-variable and anaerobic environments, such as deep tissue abscesses. In contrast, S. epidermidis strain RP62A, with its limited sugar uptake systems, exhibits slower growth under anaerobic conditions but is better suited for biofilm-associated lifestyles that emphasize persistence over rapid proliferation (Vitko et al. 2016).

Central carbon metabolism

In S. epidermidis strain 1457, the TCA cycle exhibits measurable basal activity during aerobic exponential growth in nutrient-rich conditions (Sadykov et al. 2010), probably reflecting the demand for glutamate and glutamine nitrogen. In contrast, S. aureus strain SA564 shows more pronounced repression of TCA cycle activity during exponential growth under similar conditions (Somerville et al. 2002). In both species, however, TCA cycle activity increases dramatically during the post-exponential phase following glucose depletion. Because aconitase is required for this metabolic transition in S. aureus, an aconitase mutant showed to be unable to sustain post-exponential growth and consequently entered stationary phase prematurely (Somerville et al. 2002). During this transition, the acetate that accumulates during glycolytic metabolism in the exponential phase becomes the primary carbon source feeding into the TCA cycle (Vuong et al. 2005, Somerville and Proctor 2009).

Lactate production further reflects species-specific adaptations to environmental pressures. Both species express L- and D-lactate dehydrogenases (LDHs), but S. aureus uniquely expresses a NO-inducible LDH (Ldh1) under aerobic conditions, suggesting a lower exposure or evolutionary adaptation of S. epidermidis to nitrosative stress caused by host innate immunity in aerobic environments (Richardson et al. 2008).

Regarding nitrogen metabolism, not much is known about amino acid transport in S. epidermidis. For S. aureus it was shown that it utilizes oligopeptide permeases (Opp), free amino acid transporters, and proteases to acquire nitrogen from peptides in nutrient-limited environments (Zeden et al. 2020, 2021, Lehman et al. 2023). Branched-chain amino acids (BCAAs) transport in S. aureus appears tightly linked to virulence and lipid biosynthesis, given their role as precursors for branched-chain fatty acids (Kaiser et al. 2016).

Contrary to S. epidermidis, S. aureus is auxotrophic for BCAAs, proline, arginine, and cysteine, despite encoding biosynthetic genes. These auxotrophies arise from complex regulatory controls, including glucose-dependent carbon catabolite repression mediated by the global regulator CcpA, and CodY-mediated repression of amino acid biosynthetic operons in response to intracellular metabolite levels (Pohl et al. 2009, Seidl et al. 2009, Li et al. 2010, Halsey et al. 2017, Kaiser et al. 2018, Bulock et al. 2022, Calvo et al. 2022, Jeong et al. 2022, Reslane et al. 2022).

Electron transport chain—terminal oxidases

S. epidermidis produces cytochromes aa3 and bo but apparently lacks cytochrome c in its genome. Although it carries homologs of the cydAB genes, the corresponding cytochrome bd complex has not been detected under the several conditions tested to date (Gill et al. 2005) (see also Section Staphylococcus epidermidis aerobic pathways of glucose metabolism). In contrast, S. aureus not only possesses the cydAB genes (SACOL1094–1095), but these are actively induced under respiratory stress (Uribe-Alvarez et al. 2016, Richardson 2019) . Moreover, while it is well established that S. aureus qoxADBC encodes cytochromes aa3 and bo3, where haem a and haem o are high-spin cofactors and bo3 is produced when haem a is limiting (Einarsdóttir et al. 2015, Hammer et al. 2016), the characteristics of cytochrome bo in S. epidermidis remain undefined, including whether the qoxADBC operon is responsible for its production.

Metabolic regulation

At the regulatory level, S. epidermidis shows divergent use of homologous systems. For instance, while the S. aureus two-component system SaeRS controls numerous toxins and surface proteins, only a handful of genes are commonly regulated in both species, including geh, esp, sspA, and lrgA (Pagels et al. 2010, Dmitriev et al. 2021). Moreover, SaeR regulates geh positively in S. aureus but negatively in S. epidermidis, reinforcing the notion of regulatory divergence despite structural homology.

In S. epidermidis strain 19 N, SaeR is produced at blood pH but not at skin pH (Gonçalves et al. 2022). Unlike S. aureus, in which SaeR expression is stimulated by acidic pH (Handke et al. 2008), S. epidermidis does not exhibit this response. Correspondingly, the kinetics of S. aureus growth is different from that of S. epidermidis at skin pH (Iyer et al. 2021).

Another key regulator, the SrrAB system, also exhibits functional differences. In S. epidermidis strain 1457, SrrAB responds to the presence of oxygen (Wu et al. 2015). In contrast, in S. aureus, SrrAB primarily regulates bacterial growth under anaerobic conditions, although it also contributes to bacterial fitness under oxidative and nitrosative stress (Yarwood et al. 2001, Pragman et al. 2004, Kinkel et al. 2013). This suggests that while SrrAB serves a conserved role in oxygen sensing, its regulatory outputs are tailored to each species ecological niche. Moreover, in S. aureus, SrrAB functions predominantly as a global regulator of virulence and stress response (Kinkel et al. 2013). It governs the expression of a multiple of virulence factors, including toxic shock syndrome toxin-1 (TSST-1), protein A, and components of the agr quorum sensing system (Yarwood et al. 2001, Pragman et al. 2004). By contrast, S. epidermidis SrrAB appears to have evolved a more specialized role centred on metabolic adaptation and biofilm formation rather than virulence regulation. Also, sRNAs such as RsaE exhibit species-specific functionalities. In contrast to S. epidermidis, in S. aureus, RsaE primarily acts as a metabolic modulator, with no evident role in biofilm matrix composition or population heterogeneity. In S. aureus, RsaE targets mRNAs involved in folate metabolism, arginine catabolism, and components of the TCA cycle, including rocF and other enzymes, resulting in a global downregulation of respiratory metabolism under nutrient-limited conditions (Bohn et al. 2010, Guillet et al. 2013, Bender et al. 2017, Rochat et al. 2018, Marincola et al. 2019, Barrientos et al. 2021). Unlike in S. epidermidis, RsaE is not processed into a shorter functional form, nor does it interact with lrgA or icaR, as the necessary binding motifs are absent. These observations suggest that while RsaE maintains a conserved core function related to central metabolism, its network has evolved species-specific adaptations, allowing S. epidermidis to integrate metabolic control with communal behaviours such as biofilm matrix remodelling. Furthermore, S. aureus lacks an ortholog of the S. epidermidis O-47 sRNA IcaZ, suggesting that S. epidermidis has evolved a species-specific, RNA-based mechanism to regulate its hallmark biofilm pathway (Lerch et al. 2019). The metabolic differences between these bacteria are particularly pronounced in mixed-species biofilms. For example, S. epidermidis attenuates the metabolic activity of S. aureus, resulting in diminished acid production and, consequently, lower urease activity compared to S. aureus mono-species biofilms. The molecular basis of this metabolic interference, however, remains to be elucidated (Vandecandelaere et al. 2017).

Together, these findings reveal that metabolic and regulatory networks in S. epidermidis and S. aureus have been rewired to accommodate their distinct ecological niches. S. aureus has evolved toward metabolic flexibility and enhanced virulence in response to host-imposed stresses, whereas S. epidermidis has adapted for long-term persistence, efficient biofilm formation, and fine-tuned modulation of host-derived lipids and stress signals.

Conclusion

S. epidermidis is a remarkably resilient micro-organism, metabolically adapted to thrive in both the harsh environment of the skin—characterized by low nutrient availability, reduced temperature, acidic pH, and variable oxygen levels—deeper tissues, and bloodstream. Its versatility stems from diverse central metabolic pathways and regulatory mechanisms that enable aerobic respiration, anaerobic nitrate respiration, and fermentation, as well as the formation of highly resistant biofilms, particularly those mediated by PIA.

In infection niches where glucose is the predominant carbon source, the central carbon metabolism of S. epidermidis is highly dependent on oxygen. Under aerobic conditions, the bacterium primarily utilizes the EMP pathway/glycolysis and the PPP for glucose catabolism, coupled with an active TCA cycle (Fig. 5). This leads to efficient ATP production via the aerobic ETC (Fig. 2A), maintenance of redox balance, and major acetate excretion. Notably, biofilm formation is minimal under these conditions (Fig. 5). During anaerobic nitrate respiration, glycolysis remains active, but metabolism shifts toward lactate production to maintain redox homeostasis (Fig. 5). Electrons are transferred to nitrate, a terminal electron acceptor with a lower redox potential than oxygen, resulting in reduced energy yield (Fig. 2B). Moderate biofilm production is observed, potentially associated with NO produced as a by-product of nitrate respiration, which can modulate biofilm development (Figs. 2B and 5). Under oxygen-limited conditions, which promote biofilm formation, metabolism shifts to fermentation, with glycolysis and pyruvate reduction to lactate as dominant pathways (Fig. 5). This metabolic state represents an adaptive response to the biofilm lifestyle, highlighting the flexibility of S. epidermidis in optimizing energy production and maintaining redox balance during environmental shifts, particularly in the transition from planktonic to biofilm growth.

S. epidermidis virulence relies largely on the production of PIA-based biofilms, which are closely linked to carbon flux through core metabolic pathways. The biofilm matrix also plays a central role in adaptation to immune pressures, shielding bacterial cells from immune clearance while promoting persistence and horizontal gene transfer. Furthermore, these biofilms are progressively acquiring resistance genes, partly driven by the increasing use of indwelling medical devices. In an era defined by an aging population living longer with chronic conditions, such as cardiovascular and joint diseases, this trend is expected to further increase demand for various medical devices, including pacemakers and prostheses.

This review highlights the metabolic strategies employed by S. epidermidis to survive across different environments. Although much of our current understanding derives from studies on S. aureus, emerging data emphasize important differences between the two species. Importantly, knowledge of metabolic resistance mechanisms in physiologically relevant in vivo environments remains limited.

Recognizing that S. epidermidis is more than a mere commensal, advancing our understanding of this organism will require detailed investigation of its metabolic resistance in the context of host-derived stressors. This includes in-depth analysis of its metabolic proteins, interactions with host cells and skin-associated microbiota, and a comprehensive characterization of its natural niches. Such studies are essential to unravel its pathogenic potential and inform strategies to prevent and combat S. epidermidis-associated infections.