β-ketoacyl Carrier Protein Synthase Inhibitors Analogs as Potential Antituberculotics = β-ketoacyl Carrier Protein Synthase Inhibitors Analogs as Potential Antituberculotics

다국어 초록 (Multilingual Abstract)

Tuberculosis is a significant global health threat, with one-third of the world’s population infected with its causative agent Mycobacterium tuberculosis. Fatty acid biosynthesis is one of the relatively targets in antibacterial drug discovery and most bacterial fatty acid biosynthesis enzymes are essential for viability make this a very attractive antimicrobial drug target. The enzyme β-Ketoacyl-acyl carrier protein synthase (ACPS), contributing in mycolic acids biosynthesis, has been established as promising target of novel antimycobacterial drugs. The ACPS inhibitor analogs have been investigated against Mycobacterium tuberculosis grown either in broth medium or inside macrophages. Our compounds displayed a diversity of action by acting either on extracellular Mycobacterium tuberculosis bacterial growth only, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth with very low toxicity towards host macrophages. Among the eighteen potential ACPS inhibitor analogs identified, YM-12 exhibited the best extracellular antitubercular activity (MIC50 4 ug/ml). In a macrophage model of infection, YM-12 dramatically decreased the number of intracellular Mycobacterium tuberculosis present at 5 days after infection at concentraction of 1.25 ug/ml and 2.5 ug/ml. These results might provide insights into the development of antituberculotics against Mycobacterium. Hence, the mechanism of action of the antituberculous drug on ACPS inhibitors has further investigated.