Daptomycin avoids drug resistance mediated by the BceAB transporter in

Drug-resistant bacteria are a serious threat to human health as antibiotics are gradually losing their clinical efficacy. Comprehending the mechanism of action of antimicrobials and their resistance mechanisms plays a key role in developing new agents to fight antimicrobial resistance. The lipopeptide daptomycin is an antibiotic that selectively disrupts Gram-positive bacterial membranes, thereby showing slower resistance development than many classical drugs. Consequently, it is often used as a last resort antibiotic to preserve its use as one of the least potent antibiotics at our disposal. The mode of action of daptomycin has been debated but was recently found to involve the formation of a tripartite complex between undecaprenyl precursors of cell wall biosynthesis and the anionic phospholipid phosphatidylglycerol. BceAB-type ABC transporters are known to confer resistance to antimicrobial peptides that sequester some precursors of the peptidoglycan, such as the undecaprenyl pyrophosphate or lipid II. The expression of these transporters is upregulated by dedicated two-component regulatory systems in the presence of antimicrobial peptides that are recognized by the system. Here, we investigated whether daptomycin evades resistance mediated by the BceAB transporter from the bacterial pathogen