Identification of BMVC-8C3O as a novel Pks13 inhibitor with anti-tuberculosis activity

Abstract

Given the increasing prevalence of drug-resistant tuberculosis (TB), there is an urgent demand in developing novel anti-TB medications with highly effective, safe, and utilize innovative mechanisms of action. Blocking the mycolic acid synthesis pathway is well-established to be a significant strategy in developing anti-TB drugs, and Pks13 was identified as a crucial enzyme in this process. Importantly, the modes of action of recognized Pks13 inhibitors differ from traditional anti-TB medications, highlighting Pks13 as a potential and promising target in drug development within TB treatment. In this study, we discovered a compound named BMVC-8C3O that effectively inhibited the activity of Pks13 with a 6.94 μM IC₅₀ value. The binding between BMVC-8C3O and Pks13 was validated through surface plasmon resonance (SPR) assay as well as molecular docking analysis. Moreover, the SPR assay showed that the mutation of Asn1640 and Ser1533 resulted in decreased affinity of BMVC-8C3O to Pks13. Additionally, BMVC-8C3O not only exhibited activity against Mycobacterium tuberculosis (MTB), but also displayed potential intracellular anti-TB activity in macrophages. In summary, our findings indicate that BMVC-8C3O holds great potential as a lead compound against TB.

Keywords: Anti-TB drugs; BMVC-8C3O; Pks13 inhibitor; Tuberculosis.