Daptomycin and related lipopeptides produced by fermentation, chemical modification, and combinatorial biosynthesis

Abstract

Among the structurally related ten-membered ring acidic cyclic lipopeptide antibiotics, daptomycin was the first to gain FDA approval in the USA. Daptomycin and related lipopeptides require Ca 2+ for activity, and Ca 2+ -bound daptomycin acts as a cationic peptide and interacts with the negatively charged phosphotidylglycerol (PG) in the cytoplasmic membrane to trigger its antibacterial effects. Mutants of Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, and Bacillus subtilis, which display incremental increases in resistance to daptomycin, have mutations in genes that cause reductions in the negative charge on the membrane or thickening of cell walls. Daptomycin was approved to treat skin and skin structure infections caused by Gram-positive pathogens, and bacteremia including right-sided endocarditis caused by S. aureus, but has not been approved to treat Streptococcus pneumoniae pneumonia. Many derivatives of A21978C (containing the core peptide of daptomycin) and A54145 have been generated by chemical modification or by combinatorial biosynthesis to identify antibiotics superior to daptomycin for the treatment of community-acquired pneumonia (CAP). Several compounds had antibacterial activity superior to daptomycin, but were not as active as vancomycin in a mouse model for pneumonia. Lipopeptide CB-813,315, however, was more active than daptomycin and vancomycin against Clostridium difficile in vitro, and is currently undergoing clinical trials to treat C. difficile-associated diarrhea (CDAD).