ABSTRACT
Novel cyclic lipopeptides with different acyl tails were synthesized via a semisynthetic approach. Structure-activity relationship studies revealed that lipophilicity, chain length, and the location of key aromatic functionalities of the tail modulated activity. The lead compound surotomycin exhibited significantly improved in vitro activity compared with daptomycin (MIC90 0.5 vs 2 µg/mL) against Clostridium difficile including NAP1 epidemic strains. In hamster efficacy studies, surotomycin protected animals at a dose of 0.5 mg/kg, PO.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Clostridioides difficile/drug effects , Diarrhea/drug therapy , Enterocolitis, Pseudomembranous/drug therapy , Lipopeptides/chemistry , Lipopeptides/therapeutic use , Animals , Cricetinae , Diarrhea/microbiology , Enterocolitis, Pseudomembranous/complications , Male , Microbial Sensitivity Tests , Peptides, Cyclic/chemistry , Peptides, Cyclic/therapeutic use , Structure-Activity RelationshipABSTRACT
Daptomycin was shown to interact in vitro with pulmonary surfactant leading to reduction of its antibacterial activity. We report herein the preparation and anti-staphylococcal activity of a series of daptomycin analogs with reduced pulmonary surfactant interaction by replacing tryptophan with various amino acids.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Daptomycin/analogs & derivatives , Daptomycin/pharmacology , Pulmonary Surfactants/chemistry , Staphylococcus aureus/drug effects , Tryptophan/metabolism , Daptomycin/chemistry , Microbial Sensitivity Tests , Molecular ConformationABSTRACT
Daptomycin is a lipopeptide antibiotic that kills Gram-positive bacteria by membrane depolarization. While it has long been assumed that the mode of action of daptomycin involves the formation of membrane-associated oligomers, this has so far not been experimentally demonstrated. We here use FRET between native daptomycin and an NBD-labeled daptomycin derivative to show that such oligomerization indeed occurs. The oligomers are observed in the presence of calcium ions on membrane vesicles isolated from Bacillus subtilis, as well as on model membranes containing the negatively charged phospholipid phosphatidylglycerol. In contrast, oligomerization does not occur on membranes containing phosphatidylcholine only, nor in solution at micromolar daptomycin concentrations. The requirements for oligomerization of daptomycin resemble those previously reported for antibacterial activity, suggesting that oligomerization is necessary for the activity.
