Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance

Abstract

Quinolone antimicrobials are widely used in clinical medicine and are the only current class of agents that directly inhibit bacterial DNA synthesis.Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations so as to block DNA strand passage catalysis and stabilize DNA -enzyme complexes that block the DNA replication apparatus and generate double breaks in DNA that underlie their bactericidal activity.Resistance has emerged with clinical use of these agents and is common in some bacterial pathogens.Mechanisms of resistance include mutational alterations in drug target affinity and efflux pump expression and acquisition of resistance-conferring genes.Resistance mutations in one or both of the two drug target enzymes are commonly in a localized domain of the GyrA and ParC subunits of gyrase and topoisomerase IV, respectively, and reduce drug binding to the enzyme-DNA complex.Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s).These pumps have broad substrate profiles that include other antimicrobials as well as quinolones.Mutations of both types can accumulate with selection pressure and produce highly resistant strains.Resistance genes acquired on plasmids confer low-level resistance that promotes the selection of mutational high-level resistance.Plasmid-encoded resistance is because of Qnr proteins that protect the target enzymes from quinolone action, a mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps.Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones.Q uinolones have been used extensively for a wide range of clinical applications (Owens and Ambrose 2000; Kim and Hooper 2014).Nalidixic acid, a related naphthyridone structure and the first member of the class used clinically, was discovered by George Lesher as a byproduct of chloroquine synthesis in 1962.Its use was limited to treatment of urinary tract infections and resistance emerged quickly (Lesher et al. 1962).Medicinal chemists from a number of companies, however, subsequently modified the core quinolone and related chemical scaffolds, generating compounds with greater potency, broader spectra of activity, improved pharmacokinetics, and lower frequency of development of resistance (Domagala and Hagen 2003).An important addition of a fluorine substituent at position 6 added to po-Editors: Lynn L. Silver and Karen Bush