Biomedicines 2023, 11, 371. https://doi.org/10.3390/biomedicines11020371 www.mdpi.com/journal/biomedicines Review DNA Gyrase as a Target for Quinolones Angela C. Spencer and Siva S. Panda * Department of Chemistry and Physics, Augusta University, Augusta, GA 30912, USA * Correspondence: sipanda@augusta.edu or sspanda12@gmail.com Abstract: Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. DNA gyrase is one of the primary targets of quinolones, broad-spectrum antibacterial agents and are used as a first-line drug for various types of infections. However, currently used quinolones are becoming less effective due to drug resistance. Common resistance comes in the form of mutation in enzyme targets, with this type being the most clinically relevant. Additional mechanisms, conducive to quin- olone resistance, are arbitrated by chromosomal mutations and/or plasmid-gene uptake that can alter quinolone cellular concentration and interaction with the target, or affect drug metabolism. Significant synthetic strategies have been employed to modify the quinolone scaffold and/or de- velop novel quinolones to overcome the resistance problem. This review discusses the development of quinolone antibiotics targeting DNA gyrase to overcome bacterial resistance and reduce toxicity. Moreover, structural activity relationship (SAR) data included in this review could be useful for the development of future generations of quinolone antibiotics. Keywords: quinolones; DNA gyrase; molecular docking; drug development; drug-resistance 1. Introduction For over 100 years, antibiotics have been used to clinically treat diseases, beginning in the 1910s with salvarsan, a drug designed by Paul Ehrlich to combat syphilis [1]. How- ever, over time, antimicrobial-resistant strains emerged and by 2019, antimicrobial-re- sistant pathogens were responsible for more than 4.95 million deaths, including 1.27 mil- lion deaths specifically attributable to bacterial antimicrobial resistance. This resistance is one of the leading public health threats of the 21 st century [2]. A study on antimicrobial resistance by the UK government predicts that antimicrobial resistance could be respon- sible for killing 10 million people per year by 2050 [3]. Recently, the U.S. Center for Disease Control (CDC) estimated that over 3 million Americans acquire an antimicrobial-resistant infection each year [4]. Additionally, secondary bacterial infections are significantly more complicated when the infection is associated with COVID-19 [5], resulting in higher mor- tality rates for COVID-19 patients compared to non-COVID-19 patients [6]. Based on the critical need to combat antimicrobial resistance, it is no surprise that as of 2020, the market size of antibiotics was over USD 37 billion and is expected to cross USD 45 billion by 2028 [7]. Since the first use of salvarsan, the discovery of antibiotics derived from nature, fungi, or bacteria, and the development of synthetic antibacterials, has paved the way for modern medical revolution. A closer look at the mechanism of action of antibiotics de- rived from nature reveals common molecular targets (Table 1). Beta-lactams, glycopep- tides, and other drugs, target disruption of the bacterial cell wall. Macrolides, oxazoli- dinones, streptogramins, and lincosamides target protein synthesis at the level of the 50S ribosomal subunit, while tetracyclines and aminoglycosides target the 30S small riboso- mal subunit. Ansamycins and lipiarmycins inhibit nucleic acid synthesis at the level of Citation: Spencer, A.C.; Panda, S.S. DNA Gyrase as a Target for the Quinolones. Biomedicines 2023, 11, 371. https://doi.org/10.3390/ biomedicines11020371 Academic Editors: Jean A. Boutin, Fabio Altieri and Amirata Saei Dibavar Received: 30 December 2022 Revised: 20 January 2023 Accepted: 24 January 2023 Published: 27 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/license s/by/4.0/).