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Fungal natural products targeting antimicrobial resistant Mycoplasma genitalium

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Sexually transmitted infections are a worldwide health concern, with over a million infections acquired each day. Mycoplasma genitalium is an important sexually transmitted bacterial pathogen, associated with severe upper reproductive tract sequelae in women and lower genital tract infections in both men and women. In November 2019, the CDC convened a workshop focused on STD-related pelvic inflammatory diseases in which M. genitalium was recognized as a key, but understudied, emerging pathogen that threatens the safety and welfare of the American public. The prevalence of M. genitalium in the US is higher than Neisseria gonorrhoeae and Chlamydia trachomatis in a growing number of settings with resistance to the recommended first-line treatment, azithromycin, exceeding 50% in many situation and reaching 70-90% in the most-at-risk populations. Alarmingly, resistance to moxifloxacin, recommended for macrolide-resistant strains, is increasingly detected. This spurred the CDC to include M. genitalium on its watch list in the ?2019 Antibiotic Resistance Threats in the United States? report. New drugs are needed to target what is clinically evolving into a nearly untreatable pathogen. We hypothesize that fungal natural products are an untapped source of novel antimicrobials that can be used to target M. genitalium and propose to combine our unique expertise in drug discovery and M. genitalium biology (one of only a few labs in the US that studies this fastidious organism) to develop early-stage lead compounds. We will test this hypothesis and work toward providing urgently needed bioactive drug leads through the following three specific aims: (1) test libraries of fungus-derived pure compounds and extracts for inhibition of M. genitalium growth; (2) prioritize bioactive substances, conduct assay-guided purification of inhibitory molecules, and determined their structures; and (3) investigate the activity of bioactive substances against clinical strains, as well as test for resistance development. Specifically, we will use a library of 900 purified fungal natural products, as well as 2,500 extracts produced from taxonomically diverse fungi collected over a wide range of geographical and environmental sites for activity against M. genitalium (strain G37 will be used as the assay sensor strain). Highly active pure compounds that exhibit low levels of toxicity toward human cells will be further tested against a collection of low passage antimicrobial-resistant M. genitalium clinical isolates. Upon characterizing the inhibition profiles of the active compounds as bactericidal or bacteriostatic, the potential for resistance development will be probed. We anticipate delivering 2-3 new bioactive natural-product scaffolds during each year of this R21 investigation with the goal of identifying highly promising molecules that will become the subjects of further lead compound development in the context of future R01 studies. We are unaware of prior focused efforts to systematically mine fungi and their natural products for inhibitors of M. genitalium and we have been highly encouraged by the results of our preliminary studies demonstrating that certain fungal metabolites and extracts exhibit potent inhibitory activities against this difficult-to-treat sexually-transmitted parasite.
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