Fluoroquinolone Mechanisms of Action and Resistance

Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance David C. Hooper1 and George A. Jacoby2 1Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts 02114 2Lahey Hospital and Medical Center, Burlington, Massachusetts 01805 Correspondence: [email protected] 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. www.perspectivesinmedicine.org uinolones have been used extensively for a (Lesher et al. 1962). Medicinal chemists from Qwide range of clinical applications (Owens a number of companies, however, subsequently and Ambrose 2000; Kim and Hooper 2014). modified the core quinolone and related chem- Nalidixic acid, a related naphthyridone struc- ical scaffolds, generating compounds with ture and the first member of the class used clin- greater potency, broader spectra of activity, im- ically, was discovered by George Lesher as a proved pharmacokinetics, and lower frequency byproduct of chloroquine synthesis in 1962. of development of resistance (Domagala and Its use was limited to treatment of urinary tract Hagen 2003). An important addition of a fluo- infections and resistance emerged quickly rine substituent at position 6 added to po- Editors: Lynn L. Silver and Karen Bush Additional Perspectives on Antibiotics and Antibiotic Resistance available at www.perspectivesinmedicine.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a025320 Cite this article as Cold Spring Harb Perspect Med 2016;6:a025320 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press D.C. Hooper and G.A. Jacoby tency and became the common feature of the 2013; Bax et al. 2010; Wohlkonig et al. 2010). fluoroquinolone class with the introductions In GyrA, a noncatalytic Mg2þ ion coordinated of norfloxacin in 1986 and ciprofloxacin in with four water molecules appears as a bridge 1987 that showed substantially greater potency for hydrogen bonding between quinolone and against Gram-negative bacteria. Subsequently, Ser83 and Asp87 (Wohlkonig et al. 2010), the other fluoroquinolones, such as levofloxacin, two most commonly mutated amino acids in gatifloxacin, moxifloxacin, and gemifloxacin quinolone-resistant mutants. Although quino- were developed with increased activity against lones can bind to mycobacterial gyrase in the Gram-positive bacteria. Because of their po- absence of DNA (Kumar et al. 2014), in E. coli, tency, spectrum of activity, oral bioavailability, the gyrase–DNA complex shows increases in and generally good safety profile, fluoroquino- the amount and specificity of quinolone bind- lones were used widely for a range of clinical ing relative to gyrase alone (Shen et al. 1989; indications worldwide. Although still clinically Willmott and Maxwell 1993). valuable, fluoroquinolone use has been com- Quinolones inhibit enzyme function by promised by the emergence of bacterial resis- blocking the resealing of the DNA double- tance because of mutation and acquisition of strand break, but, in addition, this process stabi- plasmid-encoded genes. In the sections that fol- lizes a catalytic intermediate covalent complex low, we review the mechanisms of quinolone of enzyme and DNA that serves as a barrier to action and resistance, which are summarized movement of the DNA replication fork (Went- in Table 1. zell and Maxwell 2000) or transcription complexes (Willmott et al. 1994) and can be con- verted to permanent double-strand DNA breaks QUINOLONE MECHANISM OF ACTION (Drlica et al. 2008), thereby functioning as Quinolones target two essential bacterial type II topoisomerase poisons (Kreuzer and Cozzarelli topoisomerase enzymes, DNA gyrase and DNA 1979). Quinolone interactions with DNA gyrase topoisomerase IV (Hooper 1997). Both en- appear to result in more rapid inhibition of zymes are heterotetramers with two subunits, DNA replication than quinolone interactions gyrase being constituted as GyrA2GyrB2 and with topoisomerase IV (Khodursky et al. 1995; topoisomerase IV as ParC2ParE2. GyrA is ho- Fournier et al. 2000), possibly relating to the mologous to ParC, and GyrB homologous to overall proximity to the DNA replication com- ParE (Wang 1996). In Staphylococcus aureus, plex of enzyme-binding sites on chromosomal topoisomerase IV subunits historically have DNA, with gyrase positioned ahead of the com- also been referred to as GrlA and GrlB. Both plex and topoisomerase IV behind it (Khodur- www.perspectivesinmedicine.org enzymes act by catalyzing a DNA double-strand sky and Cozzarelli 1998). Quinolones can differ break, passing another DNA strand through the in their potency for the two enzymes, with a break, and resealing the break (Aldred et al. general pattern among quinolones in clinical 2014). DNA strand passing occurs via domains use that there is greater activity against DNA that are localized in GyrA and ParC, whereas gyrase in Gram-negative bacteria and greater ATPase activity, which is required for enzyme activity against topoisomerase IV in Gram-pos- catalysis, occurs via domains localized in GyrB itive bacteria; but exceptions occur, and some and ParE. quinolones have similar potency against both Quinolones bind reversibly to the complex- enzymes (Blanche et al. 1996; Pan and Fisher es of DNA with gyrase and topoisomerase IV at 1997; Strahilevitz and Hooper 2005). the interface between protein and DNA near the DNA strand breaks trigger bacterial SOS active site tyrosine (Tyr122 for GyrA, Tyr120 for DNA repair responses (Piddock et al. 1990; ParC in Escherichia coli numbering), which is Drlica et al. 2008) and, to the extent that repair transiently covalently linked to DNA during is incomplete, generate quinolone bactericidal DNA strand passage, with intercalation into activity (Hiasa et al. 1996; Drlica and Zhao the cleaved DNA (Laponogov et al. 2009, 1997; Drlica et al. 2008, 2009). Inhibition of 2 Cite this article as Cold Spring Harb Perspect Med 2016;6:a025320 Downloaded from www.perspectivesinmedicine.org http://perspectivesinmedicine.cshlp.org/ Cite this article as Table 1. Mechanisms of quinolone resistance Mechanism Gene alteration Effector genes Species Other factors Altered target with Mutation in chromosomal gyrA All Primary and secondary targets vary by reduced drug structural genes gyrB drug and species with gyrA and/or Cold Spring Harb Perspect Med binding parC (grlA) Most except mycobacteria, parC most often mutated; mutations parE (grlB) Campylobacter, Treponema in both targets with additive resistance Increased expression Mutation in chromosomal MFS family: norA, norB, Staphylococcus aureus Regulators include mgrA, norG, mepR, of efflux pumps genes of transcriptional norC, mdeA, lmrS, sdrM, arlRS regulators of expression qacB(III) of chromosomally MATE family: mepA encoded pumps onOctober1,2021-PublishedbyColdSpringHarborLaboratoryPress MFS family: bmr, bmr3, blt Bacillus subtilis MFS family: lmrP Lactococcus lactis ABC family: lmrA 2016;6:a025320 MFS family: pmrA Streptococcus pneumoniae ABC family: patAB Fluoroquinolone Mechanisms of Action and Resistance ABC family: satAB Streptococcus suis MFS family: lde Listeria monocytogenes Regulator fepR MATE family: fepA RND family: acrAB-tolC Escherichia coli Regulators include marR, soxRS, rob, MFS family: emrAB-tolC, emrR mdfA RND family: acrAB-tolC Salmonella spp. RND family: oqxAB-tolC Klebsiella pneumoniae Regulators include oqxR, rarA RND family: acrAB-tolC Enterobacter aerogenes RND family: cmeABC Campylobacter jejuni MATE family: norM Vibrio parahaemolyticus RND family: mexAB-oprM, Pseudomonas aeruginosa Regulators include mexR, nfxB, nfxC, mexCD-oprJ, mexEF- mvaT, mexZ oprN, mexXY-oprM RND family: adeIJK,

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