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.

Fig. (1)

Helix-4 quinolone-binding model. The DNA-gate region is shown for a GyrA-GyrA dimer to which one fluoroquinolone molecule is bound such that the distal end of the C-7 ring (C7 tail) is near GyrA position 81 of one GyrA subunit; carboxyl and keto oxygens are near GyrA positions 87 and 83, respectively, of the other subunit.

Fig. (2)

DNA intercalation model for quinolone binding derived from clinafloxacin-topoisomerase IV-DNA crystallography. Panel A. Space-filling model for clinafloxacin. Panel B. Relative arrangement of one clinafloxacin molecule, cleaved DNA, and portions of topoisomerase IV in the co-crystal structure described by [33]. Panel C. Relative arrangement of two clinafloxacin molecules, cleaved DNA, and portions of topoisomerase IV in co-crystal structure described by [33]. Protein and DNA residues in immediate contact with, or in close proximity to FQ are indicated (ball & stick representation). ParC features (helixes III, IV) are shown in beige; a short region of ParE (maroon) shows location of ParE resistance substitutions. DNA residues flanking the drug molecules are shown in a stick representation (top strand, blue; bottom strand, magenta).

Fig. (3)

Representative 3-amino-8-methoxy-quinazoline-2,4-dione and 5-methoxy-pyrido [1,2-c]pyrimidine-1,3-dione structures.

Fig. (4)

Representative newer quinolone-class antibacterial agents found to be equipotent or near equipotent inhibitors of both DNA gyrase and topoisomerase IV. It is notable that each structure differs from early generation fluoroquinolones (e.g. ciprofloxacin and norfloxacin) by having a position-8 group other than simple aryl hydrogen.