Lysyl-Phosphatidylglycerol: A Lipid Involved in the Resistance of to Antimicrobial Peptide Activity.

Lysyl-phosphatidylglycerol (lysyl-PG) is one of the major lipids found in bacterial membranes; it is synthesized by attaching lysine to the headgroup of phosphatidylglycerol. First identified in in 1964, lysyl-PG is now recognized as a virulence factor that protects from antimicrobial agents, such as cationic antimicrobial peptides and phospholipase A2 type IIA. Under normal growth conditions, membranes are negatively charged due to a high proportion of anionic lipids, such as phosphatidylglycerol and cardiolipin. This intrinsic anionic charge helps attract positively charged antimicrobial agents to the membrane surface, increasing their disruptive activity. The presence of lysyl-PG reduces electrostatic interactions, making the membrane less susceptible to cationic agents. The biosynthesis of lysyl-PG is mediated by the multiple peptide resistance factor (MprF) enzyme, which catalyzes the modification of phosphatidylglycerol and translocation of lysyl-PG to the outer membrane in the presence of antimicrobial agents. However, several studies indicate that lysyl-PG not only responds to the presence of antimicrobial agents but can fluctuate based on environmental factors such as oxygen availability and nutrient composition. Acidic conditions and nutrient-rich media often result in increased lysyl-PG production, suggesting that bacterial membranes can be resistant to cationic antimicrobial agents even in their native state. Recent studies propose that targeting MprF to inhibit lysyl-PG biosynthesis could be a promising strategy to counter antimicrobial resistance. This review highlights the role of lysyl-PG in modulating membrane charge and its influence on antimicrobial agent efficacy and discusses a possible strategy for treatment by targeting lysyl-PG synthesis.