Quinolones: Action and Resistance Updated

Abstract

The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallography shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pathway, chromosome fragmentation stimulates excessive accumulation of highly toxic reactive oxygen species that are responsible for cell death. Quinolone resistance arises stepwise through selective amplification of mutants when drug concentrations are above the MIC and below the MPC, as observed with static agar plate assays, dynamic in vitro systems, and experimental infection of rabbits. The gap between MIC and MPC can be narrowed by compound design that should restrict the emergence of resistance. Resistance is likely to become increasingly important, since three types of plasmid-borne resistance have been reported.

Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase

“…Fluoroquinolones are broad-spectrum antibacterial agents that act by increasing levels of DNA strand breaks generated by type II topoisomerases (7)(8)(9)(10)(11)(12). Most bacterial species encode two type II enzymes, gyrase and topoisomerase IV (8,10,(12)(13)(14).…”

“…Most bacterial species encode two type II enzymes, gyrase and topoisomerase IV (8,10,(12)(13)(14). In these species, gyrase regulates the superhelical density of the bacterial chromosome and removes torsional stress that is generated ahead of DNA replication forks and transcription complexes, and topoisomerase IV primarily unknots and untangles DNA (11,15,16).…”

“…Two of these water molecules are coordinated by a conserved serine and acidic residue (located four positions downstream) in the A subunit of the enzyme. Substitutions in the residues that anchor the bridge are the most prevalent cause of quinolone resistance (10)(11)(12)(13)(22)(23)(24)(25)(26)(27). In most species, the serine is mutated far more often than the acidic residue.…”

Gene transcription from the linear plasmid pBClin15 leads to cell lysis and extracellular DNA-dependent aggregation of Bacillus cereus ATCC 14579 in response to quinolone-induced stress

“…Quinolones function by inhibiting DNA gyrase (topoisomerase II) and topoisomerase IV, preventing replication, transcription and growth (Drlica, 1999). Quinolone-mediated inhibition of these type II topoisomerases results in the formation of cleaved complexes and eventually DNA fragmentation (Champoux, 2001;Drlica et al, 2008Drlica et al, , 2009). The antimicrobial mechanism of crystal violet is less well understood and may affect more than one cellular function (Docampo & Moreno, 1990;Wakelin et al, 1981;Wolfe, 1977).…”

Identification of a novel mutation at the primary dimer interface of GyrA conferring fluoroquinolone resistance in Clostridium difficile

“…Fluoroquinolone resistance is caused by mutations in DNA gyrase or topoisomerase IV that abrogate drug-target binding [4]. In C. difficile, resistance is linked to a homoplasic Thr82Ile substitution in the quinolone resistance-determining region (QRDR) of the GyrA DNA gyrase subunit, a hallmark of globally disseminated 027/BI/NAP1 strains [5].…”