Shahila M Christie

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Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization… Show more

Francisella tularensis, the causative agent of tularemia, presents a significant biological threat and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII pathway is a viable target for the development of novel antibacterial agents treating Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided lead optimization strategy, and the determination of several co-crystal structures that confirm the binding mode of designed inhibitors. These compounds display an improved low nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity against both F. tularensis and Staphylococcus aureus and its methicillin-resistant strain (MRSA). The improvements in activity accompanying structural modifications lead to a better understanding of the relationship between the chemical structure and biological activity that encompasses both enzymatic and whole-cell activity. Show less

The rational design of pharmaceutical agents with activity against bacterial targets presents several unique challenges due to the significant differences in the target bacterial cells and the eukaryotic cells of their mammalian hosts. The structural features and cellular components commonly targeted in drug design programs are often unique to bacteria. While this provides an excellent opportunity in terms of selectivity and decreased toxicities, there are also special factors that must be… Show more

The rational design of pharmaceutical agents with activity against bacterial targets presents several unique challenges due to the significant differences in the target bacterial cells and the eukaryotic cells of their mammalian hosts. The structural features and cellular components commonly targeted in drug design programs are often unique to bacteria. While this provides an excellent opportunity in terms of selectivity and decreased toxicities, there are also special factors that must be considered, including distribution to the target, bacterial cell penetration, efflux, metabolism and elimination, and the rapid emergence of bacterial resistance. These factors can play a key role in the design of compounds intended for use against bacterial targets and the application of traditional and nontraditional screening strategies aimed at identifying such compounds. This report discusses these special issues pertaining to antibacterial drug discovery, presents practical approaches to overcoming these challenges, and highlights some recent examples of their application. Show less

Due to structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our… Show more

Due to structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motif of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds. Show less