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 mu M 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.
[1]Chinese Acad Med Sci & Peking Union Med Coll CAMS, Inst Med Biotechnol, Natl Ctr New Microbial Drug Screening, NHC Key Lab Biotechnol Microbial Drugs,State Key L, Tiantan Xili 1, Beijing 100050, Peoples R China.
[2]Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Affiliated Hosp 2, Natl Clin Res Ctr Infect Dis,Sch Med, Bougibland Rd 29, Shenzhen 518112, Peoples R China.
[3]Capital Med Univ, Beijing Chest Hosp, Beijing TB & Thorac Tumor Res Inst, Dept Pharmacol,Beijing Key Lab Drug Resistance TB, 97 Ma Chang St, Beijing 101149, Peoples R China.
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