Synthesis and Anti-mycobacterial Activity of Novel Medium-chain β-Lactone Derivatives: A Multi-Target Strategy to combat Mycobacterium abscessus and other Pathogenic Mycobacteria

Targeting the enzymes involved in mycobacterial lipid metabolism; which are mainly serine and cysteine enzymes (i.e., (Ser/Cys)-based enzymes; has emerged as a promising strategy to combat not only M. tuberculosis, but also other chronic non-tuberculous mycobacterial infections like those caused by M. marinum or M. abscessus. Among the known inhibitors of such mycobacterial enzymes, β-lactones represent promising candidates for the development of new derivatives that target lipid-processing enzymes critical for mycobacterial growth and survival. In this context, a new set of 38 lipophilic β lactone derivatives have been synthesized and tested for their anti-mycobacterial activities against the three aforementioned pathogenic mycobacteria. Remarkably, the determined MIC revealed that some VM β-lactones were able to inhibit M. abscessus growth in vitro in culture broth medium and/or inside infected macrophages. In addition, using a competitive activity-based protein profiling approach, the potential target enzymes of VM043, the most active inhibitor of extracellular bacterial growth, were further identified; thus, confirming the multi-target nature of this family of molecules.

以靶向参与分枝杆菌脂质代谢的酶类（主要为丝氨酸酶与半胱氨酸酶，即丝氨酸/半胱氨酸基酶）为策略，已成为对抗结核分枝杆菌（M. tuberculosis）以及海分枝杆菌（M. marinum）、脓肿分枝杆菌（M. abscessus）等引发的慢性非结核分枝杆菌感染的极具潜力的手段。在已知的此类分枝杆菌酶抑制剂中，β-内脂（β-lactones）是开发新型衍生物的极具潜力的候选靶点，这类衍生物可靶向对分枝杆菌生长与存活至关重要的脂质加工酶。在此研究背景下，本团队合成了38种亲脂性β-内脂衍生物，并针对上述三种致病性分枝杆菌检测了其抗分枝杆菌活性。值得注意的是，测得的最低抑菌浓度（Minimum Inhibitory Concentration，MIC）结果显示，部分VM型β-内脂可在肉汤培养基的体外环境中，以及感染巨噬细胞内部抑制脓肿分枝杆菌的生长。此外，本研究采用竞争性基于活性的蛋白质谱分析（competitive activity-based protein profiling，ABPP）方法，进一步鉴定出胞外细菌生长活性最强的抑制剂VM043的潜在靶酶，从而证实了该类分子的多靶点特性。