Front Microbiol. 2026 Apr 22;17:1815688. doi: 10.3389/fmicb.2026.1815688. eCollection 2026.
ABSTRACT
INTRODUCTION: Staphylococcus species, particularly Staphylococcus aureus, are leading opportunistic pathogens responsible for a wide range of infections, with antimicrobial resistance-including high rates of macrolide resistance-severely limiting treatment options. The msrA gene encodes the ABC-F protein MsrA, which mediates inducible resistance to 14-membered macrolides and type B streptogramins. Despite its clinical and epidemiological relevance, the evolutionary forces, selective pressures, and transmission routes shaping msrA in staphylococci remain insufficiently understood.
METHODS: Six hundred and one complete staphylococcal msrA coding sequences (CDSs) were retrieved from GenBank. Evolutionary analyses of msrA included nucleotide diversity (π), selection metrics (dN-dS , πa/πs, Tajima’s D, Fu’s Fs, FUBAR, MEME, and aBSREL), and conservation mapping using DnaSP in relation to MsrA functional domains (UniProt P23212). Linkage disequilibrium (LD) was assessed using ZnS, Za, ZZ, and Wall’s statistics. Recombination and transmission pathways were inferred using GARD, RDP4-embedded algorithms, SplitsTree network analysis, and the PHI test.
RESULTS: Forty-one msrA allelic variants were determined, with five predominant alleles accounting for approximately 90% of CDSs; allele 19 was almost exclusive to S. aureus. Nucleotide diversity was moderate (π ≈ 0.039-0.042), and strong purifying selection predominated (πa/πs ≈ 0.169; dN-dS = -0.138 ± 0.016; strongly negative Fu’s Fs), with only four codons showing evidence of episodic positive selection. Three highly conserved regions were identified, mainly overlapping the inter-domain linker and the second nucleotide-binding domain across MsrA. Moderate-to-high LD with minimal decay indicated the persistence of only a limited number of successful allelic variants. Predominant msrA alleles were largely plasmid-associated. Recombination analyses revealed frequent interspecies transfer within Staphylococcus, with S. aureus acting as a central donor to Staphylococcus chromogenes and Staphylococcus saprophyticus, as well as rare intergeneric transfers involving Citrobacter, Enterococcus, Corynebacterium, and Pseudomonas.
CONCLUSION: These findings support a dual evolutionary strategy for msrA: strong purifying selection preserves its essential ribosomal-protection function, while plasmid-mediated dissemination promotes the spread of fit alleles. S. aureus appears to be a key reservoir and vector, facilitating both interspecies and intergeneric transmission. Clinically, this underscores the need for surveillance of plasmid-borne msrA and targeted control of S. aureus reservoirs to limit resistance to macrolides and type B streptogramins.
PMID:42100691 | PMC:PMC13144154 | DOI:10.3389/fmicb.2026.1815688
