Abstract
Staphylococcus aureus ( S. aureus ) remains a major clinical challenge due to its high virulence, persistence, and remarkable capacity to develop antibiotic resistance. Survival within the host requires adaptation to oxidative and nitrosative stress generated by immune cells, which inflict extensive damage on bacterial DNA, including oxidized bases, abasic sites, and strand breaks. Under these conditions, the base excision repair (BER) pathway plays a central role in maintaining genome integrity and supporting bacterial survival under immune and antibiotic-induced stress. This review examines the organization and functional significance of BER in S. aureus , with particular emphasis on its contribution to oxidative stress tolerance, genome stability, and adaptive responses relevant to antimicrobial resistance. Comparative analysis of BER components in S. aureus and Escherichia coli ( E. coli ) highlights both conserved and species-specific features, reflecting differences in ecological adaptation, stress response strategies, and functional redundancy within DNA repair networks. Notably, the apparently lower redundancy of several BER-associated enzymes in S. aureus may create exploitable vulnerabilities for antimicrobial intervention. The therapeutic targeting of BER represents a promising but complex strategy. Inhibition of selected BER-associated enzymes may enhance antibiotic efficacy by promoting the accumulation of oxidative DNA damage and toxic repair intermediates. However, disruption of DNA repair pathways may also increase mutagenesis and accelerate adaptive evolution, potentially contributing to resistance development. Understanding the dual role of BER as both a protective mechanism and a potential source of vulnerability is therefore essential for the rational design of novel antibacterial approaches. This review highlights BER as a promising source of antibacterial targets while emphasizing that individual BER components differ substantially in their biological importance, functional redundancy, druggability and level of experimental validation. Further genetic, biochemical and pharmacological studies will be required to translate BER-targeted strategies into effective therapies against S. aureus .