In Pursuit of Next-Generation Lipopeptide Antibiotics
Can new variants of daptomycin and the polymyxins be found?
- 2018 - 2022
- Nathaniel Martin
- TTW – NACTAR programme
The aim of this proposal is to discover new lipopeptide antibiotics related to daptomycin and polymyxins by an innovative combination of computational genomics, chemical elicitation, metabolomics, and synthetic chemistry, and to prepare them for pre-clinical development. Specifically, variants will be generated that circumvent resistance and applicability issues currently faced by these important drugs. We will use functional amplicon screening to identify daptomycin- and polymyxin-like biosynthetic gene clusters across >30,000 bacterial strains, and sequence the corresponding genomes. Subsequently, we will employ structure prediction algorithms along with chemical elicitation, mass spectral networking and NMR to predict and identify the chemical structures of novel variants. These scaffolds will be further combinatorialized with a toolbox of lipopeptide tailoring enzymes from all identified gene clusters, along with synthetic chemistry approaches. The resulting molecules will be meticulously screened for pharmaceutical potential, based on mode of action, resistance profiles, cytotoxicity and stability.