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

Area of Science:

• Microbiology
• Immunology
• Drug Discovery

Background:

• Antibiotic resistance is a major global health threat, necessitating novel antimicrobial strategies.
• Multiple peptide resistance factor (MprF) confers virulence and resistance in pathogens like methicillin-resistant Staphylococcus aureus (MRSA) by modifying cell membranes.
• MprF's role in resistance to host defense peptides and antibiotics highlights it as a key therapeutic target.

Purpose of the Study:

• To develop MprF inhibitors to sensitize MRSA to existing antimicrobial agents.
• To design strategies that support the clearance of staphylococcal infections with reduced selective pressure for resistance.
• To enhance the mechanistic understanding of bacterial lipid translocation via MprF.

Main Methods:

• Development of MprF-targeting monoclonal antibodies.
• Characterization of antibody binding and blockade of the MprF flippase subunit.
• Assessment of antibody efficacy in restoring susceptibility to antibiotics and host defense peptides, and in impairing bacterial survival in phagocytes.

Main Results:

• Monoclonal antibody M-C7.1 effectively bound and blocked the MprF flippase subunit.
• M-C7.1 targeted a loop in the flippase domain exposed on both sides of the bacterial membrane, elucidating lipid translocation mechanisms.
• MRSA treated with M-C7.1 became susceptible to host antimicrobial peptides and antibiotics like daptomycin.
• Antibody treatment impaired MRSA survival within human phagocytes.

Conclusions:

• MprF inhibitors, specifically monoclonal antibodies like M-C7.1, represent a viable antivirulence approach against MRSA.
• Targeting MprF can resensitize resistant bacteria to conventional antibiotics and host defenses.
• These findings support the development of MprF inhibitors for combating staphylococcal infections and other pathogens.