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

作者：Vinayak Singh, Anna E. Grzegorzewicz, Stephen Fienberg, Rudolf Müller, Lutete Peguy Khonde, Olalla Sanz, Salvatore Alfonso, Beatriz Urones, Gerard Drewes, Marcus Bantscheff, Sonja Ghidelli‐Disse, Thomas R. Ioerger, Bhanupriya Angala, Jiuyu Liu, Richard Lee, James C. Sacchettini, Inna V. Krieger, Mary Jackson, Kelly Chibale, Sandeep R. Ghorpade · 发表于：ACS Infectious Diseases · 年份：2022 · DOI：10.1021/acsinfecdis.2c00392 · 被引用次数：5 · 研究领域：Biochemical and Molecular Research、Tuberculosis Research and Epidemiology、HIV/AIDS drug development and treatment

High Resolution Image Download MS PowerPoint Slide 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.