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Broad-spectrum antimicrobial peptide resistance by MprF-mediated aminoacylation and flipping of phospholipids

Christoph M Ernst1, Andreas Peschel

  • 1Cellular and Molecular Microbiology Division, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Elfriede-Aulhorn-Straße 6, 72076 Tübingen, Germany.

Molecular Microbiology
|February 11, 2011
PubMed

Insights

Bacteria resist cationic antimicrobial peptides (CAMPs) using the MprF enzyme, which modifies membrane phospholipids. This modification, involving lysine or alanine, creates resistance and is crucial for virulence in many pathogens.

Area of Science:

  • Microbiology
  • Biochemistry
  • Molecular Biology

Background:

  • Bacteria face constant threats from cationic antimicrobial peptides (CAMPs) produced by hosts and competitors.
  • Many pathogens, including major human ones, employ the MprF enzyme for CAMP resistance.
  • MprF modifies anionic phospholipids with amino acids, altering membrane surface charge and repelling CAMPs.

Purpose of the Study:

  • To elucidate the dual functions of the MprF enzyme in bacterial CAMP resistance.
  • To investigate the role of MprF domains in phospholipid modification and translocation.
  • To explore MprF as a potential target for novel anti-virulence therapies.

Main Methods:

  • Investigated MprF enzyme activity in modifying phosphatidylglycerol (PG) with l-lysine or l-alanine.
  • Characterized the flippase domain of MprF responsible for translocating modified phospholipids.
  • Analyzed the impact of MprF mutations on CAMP resistance and daptomycin susceptibility.

Main Results:

  • MprF synthesizes lysyl-phosphatidylglycerol (Lys-PG) or alanyl-phosphatidylglycerol (Ala-PG) from aminoacyl tRNAs and PG.
  • MprF's flippase domain is essential for translocating Lys-PG to the outer membrane leaflet for CAMP resistance.
  • Specific mprF mutations confer resistance to CAMPs and the antibiotic daptomycin, suggesting complex regulatory mechanisms.

Conclusions:

  • MprF possesses a unique dual function involving phospholipid modification and membrane translocation.
  • Understanding MprF's mechanisms is key to developing new anti-virulence drugs targeting bacterial defense systems.
  • MprF's role in daptomycin resistance warrants further investigation to combat antibiotic resistance.

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