This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bacterial infections contribute considerably to human morbidity and mortality as well as increasing healthcare costs due to emerging resistance to existing antibiotics. Recently, the discovery of novel targets, in some cases unique enzymes and pathways found only in bacteria and parasites, offer unexplored ways of combating microbial and parasitic pathogens. During our previous proposal period, we explored the structural and mechanistic features governing the biosynthesis of essential isoprenoid building blocks first via the mevalonate-independent or 2C-methyl-D-erythritol 4-phosphate (MEP) pathway. In addition, we successfully characterized both functionally and structurally a novel small molecule aromatic prenyltransferase (PTase) involved in the biosynthesis of hybrid isoprenoid - polyketide natural products some of which possess antimicrobial activity. The objective of our competing renewal is to focus our structure-function analyses of enzymes of the MEP on key control points for which new small molecule inhibitors can be designed based upon structures of protein targets determined thus far. Finally, we will expand our efforts to understand the structural and mechanistic bases for prenyl chain-length control and aromatic substrate selectivity - promiscuity in a novel family of small molecule PTases. In total, we will investigate the biosynthesis of essential isoprenoid building blocks and hybrid isoprenoid - polyketide derived antimicrobial compounds in order to address the dual threat of bio-terrorism and emerging infectious diseases.
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