NPDiscover platform identifies novel nonribosomal peptide, Edaphochelin A, killing multi-drug-resistant *Candida auris* and *C. glabrata*.

Drug-resistant candidiasis, particularly infections caused by Candida auris and Candida glabrata, represents a growing global health crisis due to limited treatment options and high mortality rates. Current antifungal drugs often face resistance, necessitating the urgent discovery of novel anti-infective agents. Natural products, especially nonribosomal peptides (NRPs), have historically been rich sources of therapeutics, including many approved anti-infectives. However, their complex biosynthesis and chemical structures make traditional discovery methods profoundly challenging, leaving a significant gap in the pipeline for new antifungal drug candidates.

Researchers developed NPDiscover, a pathogen-oriented, scalable bioinformatics platform integrating genome mining, metabolomics, and machine learning to identify novel NRPs. This platform was applied to extensive Actinobacteria datasets, leading to the discovery of edaphochelin A, a previously uncharacterized nonribosomal peptide. Structural elucidation of edaphochelin A was performed using advanced techniques such as nuclear magnetic resonance (NMR) and mass spectrometry. Its biological activity was subsequently validated through both in vitro and in vivo studies, confirming its efficacy and safety.

The NPDiscover platform successfully identified edaphochelin A, a novel nonribosomal peptide, demonstrating its utility in natural product discovery. In vitro and in vivo validation confirmed that edaphochelin A possesses potent antifungal activity. This peptide was shown to effectively kill multi-drug-resistant strains of Candida auris and Candida glabrata, two highly problematic fungal pathogens. Mechanistically, edaphochelin A exerts its fungicidal effect by disrupting respiratory chain proteins, a mode of action distinct from existing antifungal drugs. This unique mechanism suggests a potential advantage against pathogens with established resistance to conventional treatments. The comprehensive structural elucidation and biological validation established edaphochelin A as a compelling drug candidate.

Edaphochelin A effectively kills multi-drug-resistant Candida auris and Candida glabrata by disrupting respiratory chain proteins, a distinct mechanism from current antifungals.