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

Gregory S Basarab; Sandeep Ghorpade; Liezl Gibhard; Rudolf Mueller; Mathew Njoroge; Nashied Peton; Preshendren Govender; Lisa M Massoudi; Gregory Thomas Robertson; Anne J Lenaerts; Helena Ingrid Boshoff; Douglas Joerss; Tanya Parish; Thomas F Durand-Reville; Manos Perros; Vinayak Singh; Kelly Chibale

doi:10.1128/aac.02192-21

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

Antimicrob Agents Chemother. 2022 Apr 19;66(4):e0219221. doi: 10.1128/aac.02192-21. Epub 2022 Mar 10.

Authors

Gregory S Basarab^{1

2}, Sandeep Ghorpade², Liezl Gibhard¹, Rudolf Mueller², Mathew Njoroge¹, Nashied Peton², Preshendren Govender², Lisa M Massoudi³, Gregory Thomas Robertson³, Anne J Lenaerts³, Helena Ingrid Boshoff⁴, Douglas Joerss^{5

6}, Tanya Parish^{5

6}, Thomas F Durand-Reville⁷, Manos Perros⁷, Vinayak Singh^{2

8}, Kelly Chibale^{2

8}

Affiliations

¹ Drug Discovery and Development Centre (H3D), Division of Clinical Pharmacology, University of Cape Towngrid.7836.a, Observatory, Cape Town, South Africa.
² Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Towngrid.7836.a, Rondebosch, Cape Town, South Africa.
³ Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State Universitygrid.47894.36, 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 Towngrid.7836.a, 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 Mg²⁺-independent stabilization of the DNA cleavage complex with DNA gyrase and is thereby not cross-resistant with other DNA gyrase-inhibiting antibacterials, including fluoroquinolones. Compound 22 from the series was profiled broadly and showed in vitro cidality as well as intracellular activity against M. tuberculosis in macrophages. Evidence for the DNA gyrase mode of action was supported by inhibition of the target in a DNA supercoiling assay and elicitation of an SOS response seen in a recA reporter strain of M. tuberculosis. Pharmacokinetic properties of 22 supported evaluation of efficacy in an acute model of M. tuberculosis infection, where modest reduction in CFU numbers was seen. This work offers promise for deriving a novel drug class of tuberculosis agent without preexisting clinical resistance.

Keywords: DNA gyrase; Mycobacterium tuberculosis; drug resistance; spiropyrimidinetrione; tuberculosis.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

DNA Gyrase / genetics
Fluoroquinolones / pharmacology
Fluoroquinolones / therapeutic use
Humans
Mycobacterium tuberculosis*
Topoisomerase II Inhibitors / pharmacology
Tuberculosis* / drug therapy

Substances

Fluoroquinolones
Topoisomerase II Inhibitors
DNA Gyrase