Sensitizing Staphylococcus aureus to antibacterial agents by decoding and blocking the lipid flippase MprF

The pandemic of antibiotic resistance represents a major human health threat demanding new antimicrobial strategies. Multiple peptide resistance factor (MprF) is the synthase and flippase of the phospholipid lysyl-phosphatidylglycerol that increases virulence and resistance of methicillin-resistant Staphylococcus aureus (MRSA) and other pathogens to cationic host defense peptides and antibiotics. With the aim to design MprF inhibitors that could sensitize MRSA to antimicrobial agents and support the clearance of staphylococcal infections with minimal selection pressure, we developed MprF-targeting monoclonal antibodies, which bound and blocked the MprF flippase subunit. Antibody M-C7.1 targeted a specific loop in the flippase domain that proved to be exposed at both sides of the bacterial membrane, thereby enhancing the mechanistic understanding of bacterial lipid translocation. M-C7.1 rendered MRSA susceptible to host antimicrobial peptides and antibiotics such as daptomycin, and it impaired MRSA survival in human phagocytes. Thus, MprF inhibitors are recommended for new antivirulence approaches against MRSA and other bacterial pathogens.

Automated summary

The pandemic of antibiotic resistance is a major threat to human health, and new antimicrobial strategies are needed. Multiple peptide resistance factor (MprF) is a key factor that increases the resistance of methicillin-resistant Staphylococcus aureus (MRSA) and other pathogens to host defense peptides and antibiotics. In this study, monoclonal antibodies targeting MprF were developed, and an antibody called M-C7.1 was found to sensitize MRSA to antimicrobial peptides and antibiotics, as well as impair its survival in human phagocytes. These findings suggest that MprF inhibitors could be used as a new antivirulence approach against MRSA and other bacterial pathogens.