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

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Mycobacteroides Abscessus Subsp. Abscessus Mycobacterium Tuberculosis Bacteria

SUBMITTER: AUDEBERT Stephane  

LAB HEAD: Dr CAVALIER Jean-François

PROVIDER: PXD057836 | Pride | 2025-04-23

REPOSITORIES: Pride