Schematic-portfolio of potent anti-microbial scaffolds targeting DNA gyrase: Unlocking ways to overcome resistance.

Abstract

Drug development process demands validation of specific drug target impeding the Multi Drug Resistance (MDR). DNA gyrase, as a bacterial target has been in trend for developing newer antibacterial candidates due to its absence in higher eukaryotes. The fluoroquinolones are the leading molecules in the drug discovery pipeline for gyrase inhibition due to its diversity. The fluoroquinolones like levofloxacin and moxifloxacin have been listed in class A drugs for treating MDR. Gatifloxacin and ciprofloxacin also proved its efficacy against MDR TB and MDR enteric fever in adults, whereas nemonoxacin can induce anti-MDR activity of other antibiotics already suggested by studies. Though fluoroquinolones already proved its effectiveness against gyrase, other molecules viz., benzothiazinone, phenyl pyrrolamide, substituted oxadiazoles, triazolopyrimidine, arylbenzothiazole, coumarinyl amino alcohols and ciprofloxacin uracil, can inhibit the target more precisely. The structure-activity-relationships of the different scaffolds along with their synthetic strategies have been deciphered in the current review. Also, the naturally occurring compounds along with their extraction procedure have also been highlighted as potent DNA gyrase inhibitors. In addition to fluoroquinolone, the natural compounds novobiocin and simocyclinone could also inhibit the gyrase, impressively which has been designed with the gyrase structure for better understanding. Herein, ongoing clinical development of some novel drugs possessing triazaacenaphthylenes, spiropyrimidinetriones, and oxazolidinone-quinolone hybrids have been highlighted which could further assist the future generation antibiotic development corroborating gyrase as a potential target against MDR pathogens.

• Authors: Kakarla Pakeeraiah, Suvadeep Mal, Monalisa Mahapatra, Suman Kumar Mekap, Pratap Kumar Sahu, Sudhir Kumar Paidesetty
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 256 Issue Pt 2 Pg. 128402 (Nov 29 2023) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 38035955 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.