Factors Contributing to the Evolution of -Mediated β-lactam Resistance in Staphylococci: Update and New Insights From Whole Genome Sequencing (WGS)

The understanding of the mechanisms of antibiotic resistance development are fundamental to alert and preview beforehand, the large scale dissemination of resistance to antibiotics, enabling the design of strategies to prevent its spread. The -mediated methicillin resistance conferring resistance to broad-spectrum β-lactams is globally spread in staphylococci including hospitals, farms and community environments, turning ineffective the most widely used and efficient class of antibiotics to treat staphylococcal infections. The use of whole genome sequencing (WGS) technologies at a bacterial population level has provided a considerable progress in the identification of key steps that led to -mediated β-lactam resistance development and dissemination. Data obtained from multiple studies indicated that developed from a harmless core gene () encoding the penicillin-binding protein D (PbpD) from staphylococcal species of animal origin ( group) due to extensive β-lactams use in human created environments. Emergence of the resistance determinant involved distortion of PbpD active site, increase in expression, addition of regulators () and integration into a mobile genetic element (SCC). SCC was then transferred into species of coagulase-negative staphylococci (CoNS) that are able to colonize both animals and humans and subsequently transferred to of human origin. Adaptation of to the exogenously acquired SCC involved, deletion and mutation of genes implicated in general metabolism (auxiliary genes) and general stress response and the adjustment of metabolic networks, what was accompanied by an increase in β-lactams minimal inhibitory concentration and the transition from a heterogeneous to homogeneous resistance profile. Nowadays, methicillin-resistant (MRSA) carrying SCC constitutes one of the most important worldwide pandemics. The stages of development of -mediated β-lactam resistance described here may serve as a model for previewing and preventing the emergence of resistance to other classes of antibiotics.