Design, Synthesis and Evaluation of Inhibitors of the enoyl-ACP reductase from Staphylococcus aureus and Yesinia pestis

Abstract

Infectious diseases, caused by pathogenic biological agents, are the leading causes of death worldwide, especially in low-income countries. Two such pathogenic bacteria that are our centers of interest are Staphylococcus aureus, the most common cause of hospital acquired infection and Yesinia pestis, the priority pathogen that causes plague. In order to develop drugs against these pathogens, we focus on the fatty acid biosynthesis (FASII) pathway, a validated target for drug discovery due to structural differences between eukaryotic and prokaryotic fatty acid synthesis machinery. Previously, a library of diphenyl ethers synthesized by our lab exhibited potent inhibition of the enzyme enoyl-ACP reductase (FabI) that catalyzes the rate limiting step of fatty acid biosynthesis in these pathogens. Although, these inhibitors showed in vivo activity, we wanted to develop alternative inhibitors that are metabolically more stable. Thus, we synthesized a novel library of 2-pyridones inhibitors that are metabolically stable and are also hypothesized to have similar binding interaction with FabI as the diphenyl ethers. In this thesis, we report the synthesis and preliminary inhibition data for 2-pyridones as novel inhibitors of saFabI and ypFabV, the enoyl-ACP reductases from S. aureus and Y. pestis, respectively.