Is Staphylococcus Aureus a Facultative Anaerobe?

Staphylococcus aureus is a facultative anaerobe, meaning it can grow both in the presence and absence of oxygen. Some microbiologists use the equivalent term “facultative aerobe,” which describes the same capability from the opposite direction. When oxygen is available, S. aureus uses aerobic respiration for maximum energy yield; when oxygen runs out, it switches to fermentation or to anaerobic respiration using alternative electron acceptors like nitrate. That metabolic flexibility is not just a laboratory curiosity. It has direct consequences for how the bacterium causes infections, how well antibiotics work against it, and why certain S. aureus infections are so stubbornly persistent.

What “Facultative Anaerobe” Means for This Bacterium

A strict aerobe dies without oxygen. A strict anaerobe dies (or stops growing) when oxygen is present. A facultative anaerobe thrives either way, adjusting its internal chemistry to whatever is available. S. aureus fits squarely in the third category. Research on its ribonucleotide reductase genes confirmed decades ago that it is “a gram-positive facultative aerobe that can grow in the absence of oxygen by fermentation or by using an alternative electron acceptor.”¹ That capacity to reduce nitrate and ferment sugars and amino acids when oxygen is limited or absent gives S. aureus access to body sites that would starve a strictly aerobic pathogen.

How It Breathes With Oxygen

Under normal atmospheric oxygen levels, S. aureus runs a conventional aerobic respiratory chain. The final step in that chain involves heme-dependent terminal oxidases that transfer electrons to molecular oxygen, reducing it to water. The bacterium actually maintains a branched respiratory chain with two different terminal oxidases, each contributing to organ-specific colonization in animal models.² That branching may explain part of the bacterium’s ability to colonize such a wide range of tissues, from the well-oxygenated skin surface to organs with varying blood supply. Aerobic respiration generates a high proton motive force, measured at roughly 250 to 270 millivolts in cells growing at slightly acidic pH, which drives the bulk of the cell’s ATP production.³

How It Survives Without Oxygen

S. aureus has two main fallback strategies for oxygen-free environments. The first is anaerobic respiration, where it substitutes nitrate for oxygen as an electron acceptor. The bacterium carries the nitrate reductase enzyme complex NarGHJI, which reduces nitrate and can feed into further denitrification steps.⁴ Even when nitrate is not present in the environment, genes related to nitrate respiration and nitrate reduction are upregulated under anaerobic conditions, suggesting the bacterium is primed and ready to exploit nitrate the moment it encounters some.⁵

The second fallback is fermentation. When neither oxygen nor nitrate is available, S. aureus relies on glycolysis to generate ATP through substrate-level phosphorylation. It then reoxidizes NADH primarily through lactic acid fermentation when glucose is the available carbon source.⁶ The specific fermentation products shift depending on what carbon sources are on hand, but lactate is the dominant end product in glucose-rich conditions. Fermentation yields far less energy per molecule of sugar than aerobic respiration, which is why the bacterium grows more slowly without oxygen.

Under anaerobic fermentation, the proton motive force drops substantially, to around 140 to 150 millivolts, compared with the 250-plus millivolts seen during aerobic growth.³ The bacterium survives, but at a metabolic cost.

The Rex Switch That Coordinates the Transition

The shift between aerobic and anaerobic metabolism is not random. S. aureus uses a molecular sensor called Rex, a redox-sensing repressor protein that monitors the ratio of NAD+ to NADH inside the cell. When oxygen is plentiful and the electron transport chain is running, NAD+ levels are high. Rex binds to specific DNA sequences upstream of anaerobic genes and keeps them turned off. When oxygen disappears and NADH accumulates, NADH competes with NAD+ for Rex binding, the repressor loosens its grip, and genes for lactate fermentation, formate production, ethanol formation, nitrate respiration, and ATP synthesis are derepressed.⁷ Rex is considered a central regulator of anaerobic metabolism in S. aureus.

A second regulatory system, the two-component system SrrAB, complements Rex by sensing hypoxia and nitric oxide stress. SrrAB coordinates the expression of genes for cytochrome biosynthesis and assembly, anaerobic metabolism, iron-sulfur cluster repair, and nitric oxide detoxification.⁸ Rex actually regulates SrrAB expression, creating a layered control system: Rex acts as a gatekeeper that blocks maximal SrrAB expression under aerobic conditions, and releases that block when the cell shifts toward anaerobic metabolism.⁹

Slower Growth Without Oxygen, but Growth Nonetheless

The practical difference between aerobic and anaerobic growth is speed, not survival. In lab cultures at body temperature, the anaerobic generation time of S. aureus at mid-log phase was about 80 minutes, compared with 35 minutes for cells growing aerobically. Earlier studies had suggested that aerobic cultures achieve nine to seventeen times the cell density of anaerobic cultures, but work on a strain involved in food poisoning found the gap was smaller, with aerobic cultures reaching only about two to three times the density of anaerobic ones.¹⁰ That is still meaningful in terms of how fast a population expands, but it means S. aureus is not disabled without oxygen. It keeps dividing, keeps producing some toxins, and keeps causing trouble.

Why This Matters Inside the Body

Infection sites are not well-oxygenated laboratories. Both infiltrating immune cells and the bacteria themselves consume oxygen, creating pockets of deep tissue hypoxia at infected sites.¹¹ Healthy bone tissue is already low in oxygen, and S. aureus infection drives skeletal oxygen concentrations even lower. The SrrAB system turned out to be essential for bacterial survival in bone infections, confirmed by genetic screening of bacteria recovered from invasive infection models.¹²

Hypoxia does not merely permit survival. It reshapes the host-pathogen interaction. Low oxygen promotes intracellular bacterial persistence inside immune cells, drives formation of the thick abscess capsule that walls off infection, and supports the establishment of biofilms that physically block immune cell access.¹¹ The bacterium’s ability to keep metabolizing under hypoxia is therefore not just a survival trick; it actively shapes what the infection looks like.

Biofilms and the Oxygen Gradient

Biofilms, the sticky, layered communities of bacteria that form on implanted medical devices, wounds, and mucous membranes, are a setting where the facultative anaerobe lifestyle becomes critical. Microelectrode measurements through S. aureus biofilms show that oxygen drops steeply with depth. In one model, oxygen fell to less than 3% of atmospheric levels within 500 micrometers of the biofilm surface. A reporter gene for lactate dehydrogenase, a marker of anaerobic metabolism, lit up precisely in the oxygen-depleted zone, confirming that bacteria deep in the biofilm had switched to fermentation.¹³

In untreated biofilms, measurable oxygen penetrated only about 30 micrometers before being consumed. When certain antimicrobial agents were applied to the biofilm surface, killing the outermost bacteria, oxygen could penetrate deeper, reaching roughly 100 to 155 micrometers depending on the treatment.¹⁴ The implication is that the bacteria on the surface are metabolically different from those in the interior, even though they are genetically identical. Surface cells live aerobically; deep cells ferment. This metabolic heterogeneity is one reason biofilm infections are so difficult to treat.

Oxygen Levels Change Toxin Production

The bacterium’s toxin output is sensitive to how much oxygen is around. Toxic shock syndrome toxin-1 (TSST-1), the protein behind toxic shock syndrome, is essentially undetectable when S. aureus grows in strictly anaerobic conditions or at very low oxygen. Production ramps up at intermediate oxygen levels and is further amplified by the presence of carbon dioxide. In thin-film cultures, TSST-1 production increased from nearly undetectable levels under anaerobic conditions to high levels at atmospheric oxygen, with carbon dioxide boosting output by roughly tenfold.¹⁵ When bacteria that had been growing aerobically were abruptly shifted to anaerobic conditions, TSST-1 production dropped about twofold and peaked later.¹⁶

This has a clinical dimension. Bacteria buried in an oxygen-poor abscess or deep in a biofilm produce fewer toxins, which makes the immune system less likely to detect them. But if those same bacteria escape into the bloodstream or reach well-oxygenated tissue, toxin production ramps up. The metabolic flexibility that keeps them alive in hypoxic hiding spots also sets up a potential escalation when oxygen conditions change.

Antibiotic Resistance Shifts Under Anaerobic Conditions

Oxygen status also changes how susceptible S. aureus is to certain antibiotics. Aminoglycosides, a class of drugs that includes gentamicin, tobramycin, and amikacin, require active electron transport to be taken up by bacterial cells. Under anaerobic conditions, where the electron transport chain is shut down or running at low capacity, the minimum concentration of aminoglycoside needed to inhibit S. aureus growth averaged more than ten times higher than the aerobic minimum. Isolates from osteomyelitis and bloodstream infections showed an even greater increase in resistance under anaerobiosis than isolates from wounds and abscesses.¹⁷

This is not a purely academic concern. An aminoglycoside that works well against S. aureus in the oxygenated conditions of a lab test tube may perform poorly against the same bacteria sitting in an oxygen-starved biofilm on a prosthetic joint. The standard antibiotic susceptibility testing done in clinical microbiology labs is performed under aerobic conditions, which can give an overly optimistic picture of how a drug will work in the body.

Small Colony Variants and Broken Respiration

S. aureus can also produce small colony variants (SCVs), a subpopulation of slow-growing cells with distinctive traits. Many SCVs have defects in electron transport, often due to mutations in the genes for making heme or menaquinone, two molecules essential for the respiratory chain.¹⁸ Without a working respiratory chain, these cells grow slowly, produce little pigment, and make fewer toxins. They are difficult to detect in clinical cultures because they form tiny, unpigmented colonies that can be mistaken for contaminants or missed entirely.

SCVs are clinically important because they are associated with chronic, relapsing infections that resist antibiotic treatment. Their reliance on fermentation rather than respiration makes them inherently resistant to aminoglycosides. Supplementing culture media with heme can restore growth, toxin production, and normal antibiotic susceptibility in heme-auxotrophic SCVs, confirming that the defect is metabolic rather than genetic in a broader sense.¹⁹ There are multiple pathways to becoming an SCV, but respiratory deficiency is the best described clinically and experimentally.²⁰

Coping With the Immune System’s Oxygen Weapons

The interaction between S. aureus metabolism and the immune system goes beyond simply surviving low oxygen. Neutrophils, the white blood cells that respond first to bacterial invasion, attack by generating reactive oxygen species like hydrogen peroxide and superoxide. S. aureus fights back with enzymes that neutralize these molecules. Catalase activity, which breaks down hydrogen peroxide, correlates well with virulence in mouse models, and adding extra catalase to low-catalase strains increased their lethality.²¹

Exposure to hydrogen peroxide also triggers a metabolic shift toward anaerobic gene expression, even when oxygen is technically present. This shift reduces internal production of additional reactive oxygen species that would otherwise form as byproducts of aerobic respiration.²² Some S. aureus cells go further, generating hydrogen-peroxide-resistant SCVs with boosted catalase production through the SOS stress response.²³ The bacterium also subverts neutrophil function directly. During lung infections, S. aureus triggers neutrophils to produce itaconate, an anti-inflammatory metabolite that inhibits the neutrophils’ own glycolysis and oxidative burst, impairing bacterial killing.²⁴

Nitric Oxide and the Lactate Workaround

Neutrophils and macrophages also produce nitric oxide to damage invading bacteria. Nitric oxide poisons multiple components of the electron transport chain, which would be catastrophic for an organism that depends solely on aerobic respiration. S. aureus responds by expressing a specialized lactate dehydrogenase that is induced specifically by nitric oxide. This enzyme allows the cell to maintain its internal redox balance during nitric oxide stress by converting pyruvate to lactate, regenerating NAD+ without needing the electron transport chain. That lactate dehydrogenase is essential for virulence.²⁵

The story continues after that initial lactate production. The lactate produced can be recycled back to pyruvate by a lactate-quinone oxidoreductase, and that conversion generates ATP needed to fuel the uptake and use of peptides as a carbon source during nitric oxide stress. A companion enzyme, malate-quinone oxidoreductase, enables amino acid consumption under the same conditions. Both enzymes are essential for growth during nitric oxide exposure, making them potential targets for new anti-staphylococcal drugs.²⁶

Sharing Metabolism With Neighbors

S. aureus does not always infect alone. In mixed-species biofilms, its metabolic products can support the growth of neighboring bacteria. Enterococcus faecalis, another common hospital-associated pathogen, frequently co-occurs with S. aureus in wound infections. E. faecalis can respire but does not make its own heme. In dual-species biofilms, S. aureus provides the heme that activates E. faecalis respiration, boosting biofilm formation. S. aureus mutants unable to synthesize heme lose this community-building effect, while heme alone is sufficient to enhance E. faecalis biofilms. E. faecalis returns the favor with a protease that helps extract heme from hemoproteins released by S. aureus.²⁷ This metabolic cross-feeding may explain why these two species so often appear together in biofilm-associated infections and why such co-infections can be particularly stubborn to treat.