Abstract
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.
Highlights
The continuous increase of antibiotic resistance rates undermines the significance and efficacy of available antibiotics against bacterial infections [1]
Our results suggest that a specific loop between two of the transmembrane segments (TMS) of Multiple Peptide Resistance Factor (MprF) is exposed at both sides of the membrane suggesting an unusual, potentially flexible topology of this protein part, which may be involved in LysPG translocation
The hydrophobic part of S. aureus MprF appears to include 14 TMS connected by loops with predicted lengths between two and 56 amino acids [17]
Summary
The continuous increase of antibiotic resistance rates undermines the significance and efficacy of available antibiotics against bacterial infections [1]. Novel anti-infective strategies that would circumvent on one hand the difficulties in identifying new microbiota-preserving small-molecule antimicrobials and, on the other hand, the enormous selection pressures exerted by broad-spectrum antibiotics, are discussed as potential solutions against a looming post-antibiotic era [4]. Such strategies could be based for instance on therapeutic antibodies or bacteriophages, which usually have only a narrow activity spectrum. A possible direction could be the inhibition of bacterial targets that are of viable importance only during infection [5] Blocking such targets by so-called anti-virulence or anti-fitness drugs would preserve microbiome integrity and create selection pressure for resistance-conferring mutations only on invading pathogens. Interfering with bacterial virulence factors should ameliorate the course of infection and enable more effective bacterial clearance by the immune system or by antibiotics
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