PNNL

Abstract

Natural products are structurally diverse molecules with an unparalleled track record as sources of clinical drugs against cancers and microbial pathogens. Nonribosomal peptides (NRPs) constitute a natural product class that includes many clinically approved anti-infective and anti-cancer drugs. However, many challenges arise in discovering bioactive NRPs due to their complex biosynthesis and chemical structure. Here, we present NPDiscover, a pathogen-oriented and scalable bioinformatics platform for discovering NRPs that are active against drug-resistant pathogens. NPDiscover integrates genome mining, machine learning, and metabolomics analysis to discover NRPs that are potentially active against specific pathogens of interest. By applying NPDiscover to Actinobacteria datasets, we discovered an NRP, edaphochelin A, that kills urgent-threat and multi-drug-resistant Candida pathogens by reducing the respiratory chain proteins. Structural elucidation of edaphochelin A was performed using nuclear magnetic resonance and mass spectrometry techniques. Bioactivity, safety, and efficacy were determined by in vitro assays and in vivo mouse models. The efficacy, safety, and potentially distinct mode of action from existing antifungal drugs render edaphochelin A a promising drug candidate to combat the global threat of Candida pathogens. Our findings demonstrate that NPDiscover is a powerful platform for the scalable discovery of small molecules active against orphan and drug-resistant pathogens.