Abstract
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.
Highlights
Tularemia is a relatively rare infectious disease that spreads to humans through insect bites or from direct exposure to infected animals.[1]
Bacterial type II fatty acid synthesis, or FAS II, is a well-known pathway that has been targeted by many drug discovery groups.[3,4,5,6,7]
The aforementioned F. tularensis essentiality study demonstrated that F. tularensis FabI (FtFabI) was essential for growth even in the presence of exogenous long chain fatty acids.[13]
Summary
Tularemia is a relatively rare infectious disease that spreads to humans through insect bites or from direct exposure to infected animals.[1]. Our laboratory reported the identification and structural characterization of a novel series of benzimidazole FabI inhibitors as a new chemical scaffold with promising enzyme and antibacterial activity.[14, 15]
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