Bacteria’s Antioxidant Defenses Mapped in Systematic Review of 27 Studies

Bacteria survive a relentless chemical assault. Reactive oxygen and nitrogen species—superoxide anion, hydrogen peroxide, hydroxyl radicals, nitric oxide, peroxynitrite—are generated by the microbes’ own oxygen-consuming metabolism and by the immune cells that hunt them. A systematic review published in Discover Bacteria has now pulled together the evidence on how Gram-positive and Gram-negative species defend against this oxidative pressure, assessing 27 studies with formal risk-of-bias tools and mapping the enzymatic and molecular strategies that keep these organisms alive under stress, inside hosts, and during antibiotic exposure.

The review, which adhered to PRISMA 2020 reporting guidelines, searched PubMed and Embase for experimental studies published between 2010 and 2025. Two independent reviewers screened titles, abstracts, and full texts, extracting data on bacterial species, antioxidant mechanisms, stress conditions, methodology, and key findings. The organisms covered read like a roster of microbiology’s most important players: Gram-positive species included Streptococcus thermophilus, Bacillus subtilis, Bacillus velezensis, Staphylococcus aureus, Streptomyces coelicolor, Lactobacillus casei Shirota, Mycobacterium tuberculosis, and the radiation-resistant Deinococcus radiodurans. Among the Gram-negative bacteria were Escherichia coli, Francisella tularensis, Stenotrophomonas sp., Agrobacterium tumefaciens, Cupriavidus pinatubonensis, Helicobacter pylori, Klebsiella variicola, Salmonella Typhimurium, Ehrlichia chaffeensis, and Brucella abortus.

Across these taxa, the review identified three broad classes of defense. Enzymatic detoxification systems—superoxide dismutases, catalases, peroxidases, glutathione peroxidases, thioredoxins, glutaredoxins, and peroxiredoxins—convert reactive species into less harmful forms. Metal ion homeostasis limits the Fenton chemistry that free iron fuels. And small-molecule scavengers, from glutathione to carotenoids and metallothioneins, quench oxidants directly. Bacteria also repair oxidized macromolecules and deploy transcription factors such as OxyR, AphB, and CtrA to coordinate suites of antioxidant genes when stress strikes.

The first line of defense in many species is the superoxide dismutase family, which converts superoxide anion into hydrogen peroxide for downstream removal. MnSOD, encoded by the sodA gene, emerged as a dominant protective player. In one included study, a Streptococcus thermophilus sodA mutant proved hypersensitive to acid stress, while expressing the same enzyme in E. coli markedly improved survival under acid conditions; the iron-containing FeSOD did not confer comparable protection, underscoring MnSOD’s specific role in mitigating iron-mediated Fenton stress. Hydroperoxidases work alongside SODs to clear the resulting hydrogen peroxide. Stenotrophomonas sp. isolated from pesticide-laden rhizosphere soil increased catalase activity in response to peroxide, with accompanying glutathione S-transferase activity against lipid peroxidation by-products, and Salmonella and Mycobacterium rely on KatG and KatE catalase variants to survive the hydrogen peroxide produced inside macrophages.

Thiol-based systems form a second, chemically distinct layer. Peroxiredoxins such as AhpC, together with thioredoxin-like proteins and glutathione S-transferases, conferred broad resistance to reactive oxygen and nitrogen species in Francisella tularensis, Mycobacterium tuberculosis, Stenotrophomonas sp., and Ehrlichia chaffeensis, contributing to intramacrophage survival and virulence. In F. tularensis, AhpC was shown to be the principal peroxiredoxin and a virulence factor. In M. tuberculosis, the MnSOD enzyme, DoxX, and SseA form a membrane-associated complex linking superoxide detoxification to cytosolic thiol recycling; losing any component impaired mycothiol regeneration and led to oxidative damage. Another mycobacterial thioredoxin, Rv1324, enhanced persistence in macrophages—prolonging lung colonization in a mouse model while simultaneously triggering host ferroptosis and inflammation, a reminder that bacterial antioxidant success and host pathology are intertwined.

Low-molecular-weight thiols emerged as a striking case of evolutionary convergence. Most Gram-negative bacteria produce glutathione, but almost all Gram-positives do not. Instead, Firmicutes use bacillithiol and Actinomycetes rely on mycothiol. These chemically distinct molecules perform the same job: under oxidative stress they form reversible mixed disulfides with protein cysteines, shielding enzyme active sites from irreversible overoxidation. In Staphylococcus aureus, bacillithiolation of cysteine 151 protects the key metabolic enzyme Gap from oxidative damage. The review’s authors argue that this parallel thiol chemistry across divergent lineages offers highly selective drug targets, because human cells lack these bacterial redox buffers entirely.

Metal handling and extracellular strategies round out the defensive repertoire. Because free iron drives Fenton chemistry, bacteria sequester iron with ferritin and Dps-like proteins, and siderophores double as antioxidant shields. Some species even import iron deliberately: Cupriavidus pinatubonensis uses an OxyR-regulated type VI secretion system to bring in iron under oxidative stress, supporting catalase activity. Non-enzymatic tricks abound. Bacillus subtilis produces a high-molecular-weight extracellular polymeric substance with robust radical-scavenging capacity. Helicobacter pylori’s urease carries sacrificial methionine residues that quench hypochlorous acid from neutrophils and are then recycled by host methionine sulfoxide reductase. Vibrio cholerae produces hydrogen sulfide, which activates its KatB catalase and upregulates multiple antioxidant genes. Biofilm matrices, meanwhile, act as both physical barriers and chemical sponges: Salmonella biofilms overproduce colanic acid and Vi antigen, which together with matrix-associated catalase protect even adjacent catalase-deficient strains from hydrogen peroxide—a community-level shield that helps explain why chronic infections are so hard to eradicate.

The review’s clinical significance lies in turning these mechanisms into vulnerabilities. The gold drug auranofin inhibits bacterial thioredoxin reductase, depleting thiol antioxidants and sensitizing M. tuberculosis and Gram-positive pathogens to oxidative stress. Mutants of MRSA lacking bacillithiol become 16 to 60 times more sensitive to fosfomycin, since the thiol is needed to detoxify that antibiotic. Gallium mimics iron, jams iron-dependent enzymes without redox cycling, and has shown efficacy in mouse and early human trials for chronic Pseudomonas lung infections. The siderophore-linked cephalosporin cefiderocol exploits bacterial iron-uptake channels to deliver itself into Gram-negative cells, and biofilm-degrading enzymes such as DNase I, DispersinB, and the alginate lyase AlyP1400 have each dismantled matrix defenses and boosted antibiotic killing in experimental settings.

The evidence base carries caveats the authors acknowledge openly. Risk-of-bias assessment used SYRCLE’s tool for 11 animal infection models and the OHAT tool for 16 in vitro mechanistic studies. All animal studies showed high performance bias due to inadequate reporting of blinding or randomization, though all 11 demonstrated low attrition and reporting bias. Among the in vitro studies, seven carried an overall moderate risk of bias and nine were rated definitely low risk. The search was restricted to 2010–2025 publications, primarily in PubMed and Embase, and included only English-language papers, potentially missing earlier foundational work. Heterogeneity in models, stressors, and outcome measures prevented any quantitative meta-analysis, so the findings are qualitative syntheses rather than pooled effect estimates.

Even with those limitations, the review sketches a coherent framework: enzymatic scavengers form a conserved first line of defense, while lineage-specific adaptations in thiol buffers, metal handling, and extracellular matrices determine who survives in which hostile niche. The authors propose prioritizing lineage-tailored inhibitors of MnSOD or bacterial thiols, pairing ROS-amplifying agents with defense-disrupting molecules, and always targeting biofilm matrices in chronic or device-related infections. Future work, they argue, should map bacterial redox dynamics in real time within infection sites, test whether thiol- and iron-targeting agents spare beneficial commensals, model compensatory resistance mechanisms, and push nanoparticle or phage-based delivery of sensitizers and biofilm-degrading enzymes toward clinical trials in cystic fibrosis lungs, chronic wounds, and tuberculosis. Weakening redox defenses, rather than simply killing bacteria outright, may offer a resistance-sparing path against persistent and multidrug-resistant infections.

Subject of Research: Antioxidant defense mechanisms in Gram-positive and Gram-negative bacteria

Article Title: A systematic review of antioxidant defense mechanisms in bacteria species

Article References: Goumboundi, I. A., Fosu, S. A. B., Ayerkain, N. L., Siame, D., Gyamfi, B. O., Ephraim, R. K. D., & Afrifa, J. (2026). A systematic review of antioxidant defense mechanisms in bacteria species. Discover Bacteria, 3(1), Article 13. https://doi.org/10.1007/s44351-026-00048-8

Image Credits: AI Generated

DOI: 10.1007/s44351-026-00048-8

Keywords: oxidative stress, bacteria, antioxidant enzymes, superoxide dismutase, peroxiredoxins, bacillithiol, mycothiol, biofilms, antimicrobial strategies, systematic review, reactive oxygen species, iron homeostasis