7SVT

Mycobacterium tuberculosis 3-hydroxyl-ACP dehydratase HadAB in complex with 1,3-diarylpyrazolyl-acylsulfonamide inhibitor

Summary for 7SVT

• Entry DOI: 10.2210/pdb7svt/pdb
• Descriptor: HadA, (3R)-hydroxyacyl-ACP dehydratase subunit HadB, 3-[1-(4-bromophenyl)-3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-(methanesulfonyl)propanamide, ... (7 entities in total)
• Functional Keywords: mycobacterium tuberculosis, tuberculosis drug discovery, 3-hydroxyl-acp dehydratase, hadab/bc, structural genomics, tb structural genomics consortium, tbsgc, lipid binding protein, lyase-inhibitor complex, lyase/inhibitor
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 8
• Total formula weight: 132149.35

Authors

Krieger, I.V.,Sacchettini, J.C.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2021-11-19, release date: 2022-11-16, Last modification date: 2023-10-18)

Primary citation

Singh, V.,Grzegorzewicz, A.E.,Fienberg, S.,Muller, R.,Khonde, L.P.,Sanz, O.,Alfonso, S.,Urones, B.,Drewes, G.,Bantscheff, M.,Ghidelli-Disse, S.,Ioerger, T.R.,Angala, B.,Liu, J.,Lee, R.E.,Sacchettini, J.C.,Krieger, I.V.,Jackson, M.,Chibale, K.,Ghorpade, S.R.
1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in Mycobacterium tuberculosis .
Acs Infect Dis., 8:2315-2326, 2022

PubMed Abstract: 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 (). Mutations in compound -resistant 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 , in a concentration-dependent manner. Unlike known 3-hydroxyl-ACP dehydratase complex inhibitors of clinical significance, isoxyl and thioacetazone, 1,3-diarylpyrazolyl-acylsulfonamides did not require activation by EthA and thus are not liable to EthA-mediated resistance. Further, the crystal structure of a key compound in a complex with HadAB revealed unique binding interactions within the active site of HadAB, providing a useful tool for further structure-based optimization of the series.

PubMed: 36325756
DOI: 10.1021/acsinfecdis.2c00392

Experimental method

X-RAY DIFFRACTION (2.4 Å)