Design, Synthesis, and Development of 4-[2-[3,5-Bis(trifluoromethyl)anilino]thiazolo-4-yl]phenol as a Dual Inhibitor of Fatty Acid Biosynthesis (FASII) to Clear MRSA Infection

Methicillin-resistant Staphylococcus aureus (MRSA) is one of a leading cause of antibiotic-resistant bacterial infections. Based on our previous findings, we utilized thiazole-fused nootkatone hit compounds to develop a simple phenol-substituted thiazole scaffold as potent antibacterial agents, particularly active against MRSA strains. Herein, we report on the design, synthesis, and antibacterial studies of 71 compounds. In vitro studies led to the identification of 4-[2-[3,5-bis(trifluoromethyl)anilino]thiazolo-4-yl]phenol (66) as a potent antibacterial agent. This lead compound is tolerated by Caenorhabditis elegans and mice in toxicological studies. The lead candidate is highly effective in clearing MRSA infections in three in vivo models. Comprehensive serum analysis and histology studies showed negligible toxicity to mice after multiple doses of treatment. CRISPRi-mediated studies in Streptococcus mutans identified the compound's mode of action as inhibition of fatty acid biosynthesis (FAB), a finding supported by several spectroscopic studies. Robust computational studies confirmed that the lead candidate is the first dual inhibitor of BccP and FabK proteins