Design and development of FabV inhibitors as a new class of antibacterials for pathogenic Gram-negative bacteria

Due to the rapid spread and continuous threat of antimicrobial resistance (AMR), there is an urgent need for the development of novel classes of antibiotics. Despite a renewed public interest, the current pace of drug development will be insufficient to overcome the looming AMR crisis. Therefore, the identification of novel drug targets and the design of inhibitors for these targets is of primordial importance. The fatty acid synthesis (FASII) pathway in bacteria has emerged as an underexplored and vital process. The enoyl acyl carrier protein reductase (ENR), one of the enzymes in this pathway, in particular represents a promising target for antimicrobial drug development. FabI, an ENR enzyme, is known to be the target of triclosan, one of the most common additives to consumer products. In recent years, FabI inhibitors with a better bioavailability and toxicity profile have been reported as a potential new class of antibiotics. However, application in several pathogenic Gram-negative bacteria is hindered by the (co)expression of FabV, an ENR isozyme. In the current application, FabV inhibitors will be designed, optimized and tested for enzymatic as well as in vitro bacterial growth inhibition. FabV inhibitor-based antimicrobials could re-sensitize important bacterial pathogens, such as P. aeruginosa and B. mallei to FabI inhibitors, while directly inhibiting bacterial growth of species with FabV as the only ENR isozyme (e.g. V. cholerae and Y. pestis).