Identification of an Isoxazole Derivative as an Antitubercular Compound for Targeting the FadD Enzymes of Mycobacterium tuberculosis

FadD32,
a fatty acyl-AMP ligase, plays an indispensable role in
mycobacterial mycolic acid synthesis and is a validated target for
tuberculosis (TB) drug development. The crystal structure of Mycobacterium tuberculosis (Mtb)FadD32 has laid the
foundation of structure-based drug discovery against this crucial
enzyme. Here, we screened the “isoxazole” scaffold containing
molecules against MtbFadD32 and identified a compound 2,4-dibromo-6-[3-(trifluoromethyl)-1,2-oxazol-5-yl]phenol
(M1) with specific inhibitory activity against Mtb. Kinetics experiments
showed that M1 inhibits MtbFadD32 and MtbFadD28 activity. The transcriptomics
response of Mtb disclosed M1-mediated regulation of mycobacterial
decisive genes involved in cell wall synthesis, consequently creating
unfavorable conditions for Mtb survival. Further, M1 curtails the
Mtb survival in infected macrophages and reduces Mtb burden and tubercular
granulomas in a chronic infection model of BALB/c mice. Our findings
provide an effective chemical scaffold to inhibit MtbFadD32 with the
potential to inhibit multiple MtbFadD family of enzymes for further
development as a promising candidate for treating TB.