Evolution of methicillin-resistant Staphylococcus aureus: Evidence of positive selection in a penicillin-binding protein (PBP) 2a coding gene mecA

Methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) represents more and more S. aureus infections. MecA, the novel coding gene of penicillin-binding protein (PBP) 2a of MRSA, is the key resistance factor of beta-lactam, but little is known about the evolution of this gene. Given the crucial role of mecA in S. aureus physiology and beta-lactam resistance, the selective forces may contribute to adaptation of the bacteria to the special environments such as its host or antibiotics. To understand the evolution of this gene, we screened GenBank database and analyzed mecA of 249 S. aureus strains. Twenty-nine unique alleles with 26 unique amino acid sequences were identified. Phylogenetic analysis showed three main groups of mecA in the global S. aureus strains. Analysis of these alleles using codon-substitution models (M8, M3, and M2a) and likelihood ratio tests (LRTs) of the codeML package and a random-effects likelihood (REL) method of HyPhy package for the site-specific ratio of nonsynonymous to synonymous substitution rates suggested that fourteen sites in the allosteric domain of PBP2a have been subjected to strong positive selection pressure. Mutations of two positive selection sites (N146K and E239K) were reported to be essential for ceftaroline- or L-695, 256-resistant. Further study indicated that the positive selection pressure might be more likely related to the host's inflammatory or immune response during S. aureus infection. Our studies provide the first evidence of positive Darwinian selection in the mecA of S. aureus, contributing to a better understanding of the adaptive mechanism of this bacterium.