Protective Effect of Qnr on Agents Other than Quinolones That Target DNA Gyrase

Abstract

bQnr is a plasmid-encoded and chromosomally determined protein that protects DNA gyrase and topoisomerase IV from inhibition by quinolones. Despite its prevalence worldwide and existence prior to the discovery of quinolones, its native function is not known. Other synthetic compounds and natural products also target bacterial topoisomerases. A number were studied as molecular probes to gain insight into how Qnr acts. Qnr blocked inhibition by synthetic compounds with somewhat quinolone-like structure that target the GyrA subunit, such as the 2-pyridone ABT-719, the quinazoline-2,4-dione PD 0305970, and the spiropyrimidinetrione pyrazinyl-alkynyl-tetrahydroquinoline (PAT), indicating that Qnr is not strictly quinolone specific, but Qnr did not protect against GyrA-targeting simocyclinone D8 despite evidence that both simocyclinone D8 and Qnr affect DNA binding to gyrase. Qnr did not affect the activity of tricyclic pyrimidoindole or pyrazolopyridones, synthetic inhibitors of the GyrB subunit, or nonsynthetic GyrB inhibitors, such as coumermycin A1, novobiocin, gyramide A, or microcin B17.Thus, in this set of compounds the protective activity of Qnr was confined to those that, like quinolones, trap gyrase on DNA in cleaved complexes. Qnr was discovered as a plasmid-encoded protein that reduces susceptibility to quinolones (1). Quinolones are synthetic compounds that target the essential bacterial enzymes DNA gyrase and topoisomerase IV, homologous tetramers composed of GyrA and GyrB or ParC and ParE subunits, respectively, that introduce negative supercoils or unknot and decatenate the DNA helix with energy from ATP hydrolysis (2).Qnr is a pentapeptide repeat protein that blocks quinolone inhibition of both topoisomerases and binds to each of their subunits as well as to the holoenzymes (3-5). Many bacteria have qnr-like genes on the chromosome, some, especially in aquatic bacteria, closely related to plasmid-determined qnr varieties (6-8). The native function of these proteins, which clearly antedate the clinical use of quinolones, is not known.A number of other agents target topoisomerases. Well-studied natural products include coumermycin A1 (9, 10), gyramide A (11), microcin B17 (12), novobiocin (9, 10), and simocyclinone D8 (13,14). From mutational and other studies the sites of action of many of these agents are known. For example, the primary site of resistance mutations for quinolones in Gram-negative bacteria is a region on the GyrA subunit known as the quinolone resistance-determining region (QRDR) (15), while novobiocin targets ATPase activity of the GyrB subunit (9). Qnr does not protect against novobiocin inhibition of gyrase (16), but the protective effect of Qnr on other natural products is not yet known. Medicinal chemists have synthesized synthetic compounds of various structures intended to act on gyrase at sites different from those directly affected by quinolones, especially the GyrB subunit. Whether Qnr protects gyrase from such compounds has not been investigated. The aim of this study was to...

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“…Based on the results gotten from this study, all the selected compounds are considered as specific ligand of DNA gyrase with high docking scores (Figure 3), hence they possess antimicrobial properties. This is in agreement with reported results of previous studies [6,23,24].…”

Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance

“…Many naturally occurring antibiotics and synthetic agents also target DNA gyrase. Qnr protects against compounds with a somewhat quinolone-like structure (Jacoby et al 2015), for example, 2-pyridone (Flamm et al 1995), quinazoline-2,4-dione (Huband et al 2007), or spiropyrimidinetrione (Kern et al 2011), so it is not strictly quinolone-specific. Qnr, however, does not block agents acting on the GyrB subunit, and it also does not block simocyclinone D8, which, like quinolones, binds to the amino terminus of GyrA and blocks DNA binding (Hearnshaw et al 2014).…”

Transferable Mechanisms of Quinolone Resistance from 1998 Onward

“…It was observed that Qnr also confers slight protection against 2-pyridones, quinazoline-2,4-diones (both of which are structurally closely related to quinolones), and spiropyrimidinetriones but has no protective effect against other topoisomerase type II-targeting molecules such as aminocoumarins (coumermycin A1, novobiocin, and simocyclinone D8), gyramide A, microcin B17, pyrazolopyridones, or tricyclic pyrimidoindoles (310).…”