2. Academic Validation
  3. Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

  • J Med Chem. 2022 May 12;65(9):6903-6925. doi: 10.1021/acs.jmedchem.2c00266.
Preshendren Govender 1,  Rudolf Müller 1,  Kawaljit Singh 1,  Virsinha Reddy 1,  Charles J Eyermann 1,  Stephen Fienberg 1,  Sandeep R Ghorpade 1,  Lizbé Koekemoer 2,  Alissa Myrick 2,  Dirk Schnappinger 3,  Curtis Engelhart 3,  Jaclynn Meshanni 3,  Jo Ann W Byl 4,  Neil Osheroff 4 5 6,  Vinayak Singh 1 2,  Kelly Chibale 1 2,  Gregory S Basarab 1 7
Affiliations

Affiliations

  • 1 Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, Cape Town 7701, South Africa.
  • 2 Drug Discovery and Development Centre (H3D) 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, Rondebosch, Cape Town 7701, South Africa.
  • 3 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States.
  • 4 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 5 Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 6 VA Tennessee Valley Healthcare System, Nashville, Tennessee 37212, United States.
  • 7 Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, Cape Town, 7935, South Africa.
PMID: 35500229 DOI: 10.1021/acs.jmedchem.2c00266
Abstract

New Antibiotics with either a novel mode of action or novel mode of inhibition are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug-resistant Mycobacterium tuberculosis (Mtb), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against Mtb DNA gyrase (e.g., compound 42 with IC50 = 2.0) and lower Mtb minimum inhibitor concentrations (0.49 μM for 42). Notably, 42 and analogues showed selective Mtb activity relative to representative Gram-positive and Gram-negative bacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA, while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with Mtb DNA gyrase was developed, and a structural hypothesis was built for structure-activity relationship expansion.

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