Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones

Author:

Basarab Gregory S.12ORCID,Ghorpade Sandeep2,Gibhard Liezl1ORCID,Mueller Rudolf2,Njoroge Mathew1,Peton Nashied2,Govender Preshendren2,Massoudi Lisa M.3,Robertson Gregory Thomas3ORCID,Lenaerts Anne J.3,Boshoff Helena Ingrid4,Joerss Douglas56,Parish Tanya56ORCID,Durand-Reville Thomas F.7,Perros Manos7,Singh Vinayak28ORCID,Chibale Kelly28

Affiliation:

1. Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, University of Cape Town, Observatory, Cape Town, South Africa

2. Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, South Africa

3. Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA

4. Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA

5. Infectious Disease Research Institute, Seattle, Washington, USA

6. Center for Global Infectious Disease, Seattle Children’s Research Institute, Seattle, Washington, USA

7. Entasis Therapeutics, Inc., Waltham, Massachusetts, USA

8. South African Medical Research Council Drug Discovery and Development Research Unit, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, Cape Town, South Africa

Abstract

Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves Mg 2+ -independent stabilization of the DNA cleavage complex with DNA gyrase and is thereby not cross-resistant with other DNA gyrase-inhibiting antibacterials, including fluoroquinolones.

Funder

Bill and Melinda Gates Foundation

HHS | NIH | National Institute of Allergy and Infectious Diseases

South African Medical Research Council

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference44 articles.

1. WHO. 2021. Global tuberculosis report 2021. https://www.who.int/publications/i/item/9789240037021. Accessed 10 January 2021.

2. Global burden of tuberculosis: where we are and what to do

3. WHO. 2014. International standards for tuberculosis care, 3rd ed. World Health Organization, Geneva, Switzerland.

4. MDR/XDR-TB management of patients and contacts: Challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network

5. Strategies to Combat Multi-Drug Resistance in Tuberculosis

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