Structural modification of natural products through the addition of various chemical groups onto the natural product skeleton is an attractive strategy to develop pharmacologically active molecules with differing properties. However, the structural complexities of several macrocyclic peptide natural products present significant challenges in their chemical modification. Herein, we propose to exploit the inherent promiscuity of a tryptophan modifying enzyme CdpNPT to structurally modify a macrocyclic peptide drug, daptomycin and generate analogs with potential enhanced activities. Specifically, we intend to generate 20-30 new daptomycin analogs via our innovative chemoenzymatic platform that includes the synthesis of diverse array of alkyl-pyrophosphate analogs as alkyl donors. The new daptomycin analogs will then be structurally characterized and screened for antibacterial potency against a representative set of bacterial strains including daptomycin resistant strains. The outcome of this study is expected to provide a systematic SAR on the size and type of attachment of chemical groups on daptomycin as a means to generate improved daptomycin analogs with enhanced antibacterial activity.
Daptomycin is a bactericidal antibiotic of last-resort used to treat infections by many resistant bacteria including Methicillin-resistant Staphylococcus aureus. Despite its potent bactericidal activity against many Gram-positive bacteria, there have been increasing reports of daptomycin resistance. The research aims to utilize an innovative chemoenzymatic approach to develop daptomycin analogs for their potential use against daptomycin resistant infections.
