Producing Novel Biosynthetic Therapeutics from Extreme Microbiomes

This project is a unique metagenomic evaluation of under-studied extremophilic microbiome natural products (NPs), with the goal of discovering novel antibiotic biowarfare agent (BWA) countermeasures. A metagenomic biosynthetic gene cluster library from extremophilic sources was created, sequenced, analyzed, and exploited to produce several broad-spectrum antibiotic extracts during the Phase I effort. A novel platform for extremophilic microbiome drug discovery (EMDD) was created as well and will be expanded during the Phase II effort. These extracts will be purified and biochemically characterized before testing in vitro against BWAs. Cytotoxicity and mechanism of action studies will be conducted using in vitro and in silico methods. The leads will be optimized by a structure-activity relationship expansion study, which will generate a series of improved analogues for further in vitro screening. The best lead compounds will be tested for in vivo efficacy against priority bacterial BWAs. The goal is to discover a novel antibiotic with efficacy of >50% survival in a lethal challenge mouse model for subsequent preclinical studies and FDA investigational new drug application.