Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones.
Gregory S BasarabSandeep GhorpadeLiezl GibhardRudolf MuellerMathew NjorogeNashied PetonPreshendren GovenderLisa M MassoudiGregory Thomas RobertsonAnne J LenaertsHelena Ingrid BoshoffDouglas JoerssTanya ParishThomas F Durand-RevilleManos PerrosVinayak SinghKelly ChibalePublished in: Antimicrobial agents and chemotherapy (2022)
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. 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.
Keyphrases
- mycobacterium tuberculosis
- circulating tumor
- cell free
- single molecule
- pulmonary tuberculosis
- nucleic acid
- hiv aids
- circulating tumor cells
- machine learning
- hepatitis c virus
- crispr cas
- drug induced
- human immunodeficiency virus
- transcription factor
- extracorporeal membrane oxygenation
- dna binding
- antiretroviral therapy
- single cell