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Decoding and blocking the bacterial lipid flippase MprF yields a novel anti-virulence strategy

The pandemic of antibiotic resistance represents a major human health threat demanding new antimicrobial strategies. MprF is synthase and flippase of the phospholipid lysyl-phosphatidylglycerol that increases virulence and resistance of methicillin-resistant Staphylococcus aureus (MRSA) and other pathogens. With the aim to design an anti-virulence strategy for staphylococci causing minimal antibiotic selection pressure, we developed MprF-targeting monoclonal antibodies which bound and inhibited the MprF flippase. Antibody M-C7.1 targeted a loop in the enigmatic flippase domain that proved to be exposed at both sides of the bacterial membrane, thereby providing mechanistic insights into bacterial lipid translocation. M-C7.1 rendered MRSA susceptible to host antimicrobial peptides and antibiotics such as daptomycin. Moreover, it impaired MRSA survival in human phagocytes and virulence in a murine infection model, which recommends MprF inhibitors for new anti-MRSA approaches. MprF-directed monoclonal antibodies provide a proof of concept for development of precisely targeting anti-virulence drugs which block bacterial defense mechanisms.