Persephacin Is a Broad-Spectrum Antifungal Aureobasidin Metabolite That Overcomes Intrinsic Resistance in Aspergillus fumigatus

Fungipose a persistent threat to humankind with worryingindicationsthat emerging and re-emerging pathogens (e.g., Candida auris, Coccidioides spp., drug-resistant Aspergilli,and more) exhibit resistance to the limited number of approved antifungals.To address this problem, our team is exploring endophytic fungi asa resource for the discovery of new antifungal natural products. Therationale behind this decision is based on evidence that endophytesengage with plants in mutualistic relationships wherein some fungiactively participate by producing chemical defense measures that suppresspathogenic microorganisms. To improve the odds of bioactive metabolitediscovery, we developed a new hands-free laser-cutting system capableof generating >50 plant samples per minute that, in turn, enabledour team to prepare and screen large numbers of endophytic fungi.One of the fungal isolates obtained in this way was identified asan Elsinoe'' sp. that produced a unique aureobasidinanalogue, persephacin (1). Some distinctive featuresof 1 are the absence of both phenylalanine residues combinedwith the incorporation of a novel amino acid residue, persephanine(9). Compound 1 exhibits potent antifungaleffects against a large number of pathogenic yeast (including severalclinical C. auris strains), as well as phylogeneticallydiverse filamentous fungi (e.g., Aspergillus fumigatus). In an ex vivo eye infection model, compound 1 outperformed standard-of-care treatments demonstrating theability to suppress fluconazole-resistant Candida albicans and A. fumigatus at a concentration (0.1% solution)well below the clinically recommended levels used for fluconazoleand natamycin (2% and 5% solutions, respectively). In 3D tissue modelsfor acute dermal and ocular safety, 1 was found to benontoxic and nonirritating at concentrations required to elicit antifungalactivity. Natural product 1 appears to be a promisingcandidate for further investigation as a broad-spectrum antifungalcapable of controlling a range of pathogens that negatively impacthuman, animal, and plant health.

Automated summary

Fungi pose a persistent threat to humankind as emerging and re-emerging pathogens exhibit resistance to approved antifungals. To address this problem, researchers are exploring endophytic fungi for the discovery of new antifungal natural products, based on their mutualistic relationship with plants and their ability to produce chemical defense measures.