Altered PBP4 and GdpP functions synergistically mediate MRSA-like high-level, broad-spectrum β-lactam resistance inStaphylococcus aureus

Abstract

AbstractInfections caused byStaphylococcus aureusare a leading cause of mortality worldwide.S. aureusinfections caused by Methicillin-ResistantStaphylococcus aureus(MRSA) are particularly difficult to treat due to their resistance to Next Generation β-lactams (NGB) such as Methicillin, Nafcillin, Oxacillin etc. Resistance to NGBs, which is alternatively known as broad-spectrum β- lactam resistance is classically mediated by PBP2a, a Penicillin-Binding Protein encoded bymecA(ormecC) in MRSA. Thus, presence ofmecgenes amongS. aureusserves as the predictor of resistance to NGBs and facilitates determination of the proper therapeutic strategy for a staphylococcal infection. Although far less appreciated,mecAdeficientS. aureusstrains can also exhibit NGB resistance. These strains, which are collectively termed as Methicillin-Resistant Lackingmec(MRLM) are currently being identified in increasing numbers among natural resistant isolates ofS. aureus. The mechanism/s through which MRLMs produce resistance to NGBs remains unknown. In this study, we demonstrate that mutations that alter PBP4 and GdpP functions, which are often present among MRLMs can synergistically mediate resistance to NGBs. Furthermore, our results unravel that this novel mechanism potentially enables MRLMs to produce resistance towards NGBs at levels comparable to that of MRSAs. Our study, provides a fresh new perspective about alternative mechanisms of NGBs resistance, challenging our current overall understanding of high-level, broad-spectrum β-lactam resistance inS. aureus. It thus suggests reconsideration of the current approach towards diagnosis and treatment of β-lactam resistantS. aureusinfections.