SensitizingStaphylococcus aureusto antibacterial host defense by decoding and blocking the lipid flippase MprF

Abstract

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.

Identification of a novel cationic glycolipid inStreptococcus agalactiaethat contributes to brain entry and meningitis

“…These data suggest that MprF is especially important in the niches GBS colonizes. The decreased in vivo pathogenicity of the ΔmprF mutant presented in this work, identifies the GBS MprF as a strong candidate for targeting by antimicrobial strategies recently described in S. aureus (17,51). The fact that Lys-Glc-DAG is a unique and major membrane component of GBS holds promise that Lys-Glc-DAG could be utilized as a specific and efficient molecular biomarker for a rapid GBS diagnostic test that would not rely on culturing procedures or nucleic acid amplification.…”

Interference with lipoprotein maturation sensitizes methicillin-resistantStaphylococcus aureusto human group IIA secreted phospholipase A2and daptomycin

“…dltABCD, graRS, and mprF overlap for daptomycin and hGIIA [14,[22][23][24]57]. We therefore investigated whether lspA deletion affected daptomycin resistance.…”

“…Correspondingly, the identified S. aureus resistance genes, i.e. dltABCD, graRS , and mprF overlap for daptomycin and hGIIA [14, 22-24, 57]. We therefore investigated whether lspA deletion affected daptomycin resistance.…”