biostudies-literatureSingh VNational Institute of Allergy and Infectious DiseasesDepartment of Science and Innovation, South AfricaNIAID NIH HHSWelch FoundationUniversity of Cape TownBill and Melinda Gates FoundationSouth African Medical Research Council2315-2326https://www.ebi.ac.uk/biostudies/studies/S-EPMC9673142biostudies-literatureUnknown8(11)Alternative mode-of-inhibition of clinically validated targets is an effective strategy for circumventing existing clinical drug resistance. Herein, we report 1,3-diarylpyrazolyl-acylsulfonamides as potent inhibitors of HadAB/BC, a 3-hydroxyl-ACP dehydratase complex required to iteratively elongate the meromycolate chain of mycolic acids in <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). Mutations in compound <b>1</b>-resistant <i>Mtb</i> mutants mapped to HadC (Rv0637; K157R), while chemoproteomics confirmed the compound's binding to HadA (Rv0635), HadB (Rv0636), and HadC. The compounds effectively inhibited the HadAB and HadBC enzyme activities and affected mycolic acid biosynthesis in <i>Mtb</i>, in a concentration-dependent manner. Unlike known 3-hydroxyl-ACP dehydratase complex inhibiACS infectious diseases1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in <i>Mycobacterium tuberculosis</i>.PMC9673142P01AI095208OPP1095631A-0015AI130929P01 AI095208OPP1066878R21 AI130929AI153477R21 AI153477Alfonso SLiu JJackson MSanz OMuller RGrzegorzewicz AELee REKrieger IVGhorpade SRSacchettini JCChibale KBantscheff MGhidelli-Disse SKhonde LPAngala BDrewes GIoerger TRFienberg SUrones BSingh Vfalse1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in <i>Mycobacterium tuberculosis</i>.Alternative mode-of-inhibition of clinically validated targets is an effective strategy for circumventing existing clinical drug resistance. Herein, we report 1,3-diarylpyrazolyl-acylsulfonamides as potent inhibitors of HadAB/BC, a 3-hydroxyl-ACP dehydratase complex required to iteratively elongate the meromycolate chain of mycolic acids in <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>). Mutations in compound <b>1</b>-resistant <i>Mtb</i> mutants mapped to HadC (Rv0637; K157R), while chemoproteomics confirmed the compound's binding to HadA (Rv0635), HadB (Rv0636), and HadC. The compounds effectively inhibited the HadAB and HadBC enzyme activities and affected mycolic acid biosynthesis in <i>Mtb</i>, in a concentration-dependent manner. Unlike known 3-hydroxyl-ACP dehydratase complex inhibi2022-01-01T00:00:00Z2022 Nov2026-05-28T07:03:04.957Z2025-02-19T04:20:11.656ZS-EPMC96731423632575610.1021/acsinfecdis.2c00392