The ability of microbes, especially bacteria, to produce biologically active molecules that can form the basis of therapeutic agents to confront important human pathogens forms the overall premise of this CETR application. The microbial producers will be symbiotic bacteria from a variety of niches. The assays that will lead to the discovery of potential therapeutic agents will focus on multidrug resistant Gram-negative bacteria and systemic fungal pathogens. The Chemistry Core will be responsible for converting the activity discovered in biological assays into purified active molecules with known structures in sufficient amounts that secondary functional assays, structure-activity studies, and target identification can be addressed. This overall goal will be accomplished with four tasks, which are described in much greater detail in a later section of the proposal. Task 1: Produce symbiotic microbe metabolite fractions for dereplication and in vitro efficacy and safety testing. Task 2: Scale-production of promising fraction for in vivo testing and structural elucidation. Task 3: Purify and structurally characterize the active molecule/s. Task 4: Large-scale production for advanced in vivo PK/PD and mechanism of action determination.
