1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in Mycobacterium tuberculosis

  • ACS Infect Dis. 2022 Nov 11;8(11):2315-2326. doi: 10.1021/acsinfecdis.2c00392.
Vinayak Singh  1  2 ,  Anna E Grzegorzewicz  3 ,  Stephen Fienberg  1 ,  Rudolf Müller  1 ,  Lutete Peguy Khonde  1 ,  Olalla Sanz  4 ,  Salvatore Alfonso  4 ,  Beatriz Urones  4 ,  Gerard Drewes  5 ,  Marcus Bantscheff  5 ,  Sonja Ghidelli-Disse  5 ,  Thomas R Ioerger  6 ,  Bhanupriya Angala  3 ,  Jiuyu Liu  7 ,  Richard E Lee  7 ,  James C Sacchettini  8 ,  Inna V Krieger  8 ,  Mary Jackson  3 ,  Kelly Chibale  1  2 ,  Sandeep R Ghorpade  1
Affiliations
  • 1. Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch7701, South Africa.
  • 2. South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch7701, South Africa.
  • 3. Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado80523-1682, United States.
  • 4. Global Health Pharma Research Unit, GlaxoSmithKline, Severo Ochoa 2, Tres Cantos, Madrid28760, Spain.
  • 5. Cellzome GmbH · A GSK Company, Meyerhofstrasse 1, Heidelberg69117, Germany.
  • 6. Department of Computer Science and Engineering, Texas A&M University, College Station, Texas77843, United States.
  • 7. Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee38105, United States.
  • 8. Texas A&M University, Department of Biochemistry and Biophysics, ILSB 2138, 301 Old Main Dr, College Station, Texas77843-3474, United States.
PMID: 36325756 DOI: 10.1021/acsinfecdis.2c00392
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 Mycobacterium tuberculosis (Mtb). Mutations in compound 1-resistant Mtb 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 Mtb, 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 Mtb HadAB revealed unique binding interactions within the active site of HadAB, providing a useful tool for further structure-based optimization of the series.

Keywords
1,3-diarylpyrazolyl-acylsulfonamides; 3-hydroxyl-ACP dehydratase; FASII pathway; Mycobacterium tuberculosis; tuberculosis drug discovery.
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