Mechanistic insights into the C₅₅-P targeting lipopeptide antibiotics revealed by structure–activity studies and high-resolution crystal structures

Abstract

Structural and mechanistic studies give new insights into calcium-dependent lipopeptide antibiotics that target C55-P.

Studies on daptomycin lactam‐based analogues

“…On the other hand, we have not investigated if the mechanism of action of the lactam analogues has changed when the ester bond was switched to an amide bond. In the calcium dependent antibiotic (CDA) family, members with lactam structures were found to kill bacteria by binding to undecaprenol phosphate (C 55 ‐P), a universal carbohydrate carrier involved in several cell envelope biosynthetic pathways such as lipid II synthesis 36,37 . A possible shift in MOA of the daptomycin lactam‐based analogues may also explain the nonadditive effect observed when multiple effective modifications of daptomycin were performed along with the ester bond modification.…”

Targeting membrane-bound bacterial cell wall precursors: a tried and true antibiotic strategy in nature and the clinic

“…38 Recently, our group also prepared a series of hybrid CDAs to probe the impact of structural variations at residues 4, 9, and 10, which differ between the friulimicin/amphomycin and laspartomycin classes. 49 A surprising result from this investigation was that among lipopeptides resembling friulimicin/ amphomycin, the introduction of Val at position 10 was strongly favoured compared to Ile at the same position, leading to an 8-fold lower MIC against methicillin-resistant Staphylococcus aureus (MRSA). The profound impact on activity associated with this remarkably subtle structural change was rationalised via analysis of the crystal structures of these analogues bound to C 10 P. The slightly less bulky Val10 side chain (found naturally in the amphomycin/friulimicin class) allows for optimal packing of the peptide in the crystal structure allowing for enhanced interaction with the polyprenyl phosphate bacterial target, and is hypothesized to underscore the increased antibacterial activity observed.…”

“…The profound impact on activity associated with this remarkably subtle structural change was rationalised via analysis of the crystal structures of these analogues bound to C 10 P. The slightly less bulky Val10 side chain (found naturally in the amphomycin/friulimicin class) allows for optimal packing of the peptide in the crystal structure allowing for enhanced interaction with the polyprenyl phosphate bacterial target, and is hypothesized to underscore the increased antibacterial activity observed. 49 MX-2401 is a semisynthetic analogue of amphomycin that was taken into preclinical development for the treatment of serious Gram-positive infections in 2011. 50 MX-2401 is structurally different from amphomycin in two ways.…”

β-Lactams from the Ocean

“…Taromycin A is recognized immediately as a marine-derived cognate structure of the Gram-positive antibiotic, daptomycin [ 84 , 85 ]. Daptomycin interferes with bacterial peptidoglycan biosynthesis by complexation with its biosynthetic intermediates [ 86 , 87 ]. Daptomycin is used increasingly in the clinic against serious Gram-positive bacterial infections.…”