Executive Summary : | Antimicrobial resistance (AMR) is a growing threat to human health, with multidrug-resistant pathogens such as Enterobacter, staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter causing a significant proportion of nosocomial infections. Mycobacterium tuberculosis infections have also become multi-drug resistant, making tuberculosis one of the top 10 causes of death. Despite the availability of antibiotics to treat these infections, more bacterial and mycobacterial strains have developed resistance to these drugs. Developing new antibacterial and antimycobacterial agents that act on unexploited therapeutic targets is crucial to avoid known resistance mechanisms. Enoyl-ACP reductase (ENR) is an important enzyme in the FAs-II pathway, which catalyzes the reduction of a double bond in enoyl-ACP to acyl-ACP. FabI, a major enoyl reductase enzyme, is widely distributed in various microorganisms and has been designed to have broad-spectrum antibacterial activity. Efforts have been devoted to developing effective FabI-targeting antibiotics, leading to potent FabI inhibitors with diverse chemical structures. Recent developments have led to modified derivatives of AFN-1252, such as AFN-1252-NH3 and Debio-1452-NH3, which possess a broad spectrum of activity. Fabimycin, a derivative of Debio-1452-NH3, has broad spectrum antibacterial activity and low resistance frequency, making it a promising candidate for translation. In the current project proposal, new broad spectrum FabI inhibitors will be designed based on the understanding of crystal structural information and sAR of promising compounds. |