Mechanism of action of and resistance to quinolones.
Bottom Line: The evolution of quinolones to more potent molecules was based on changes at positions 1, 6, 7 and 8 of the chemical structure of nalidixic acid.The acquisition of quinolone resistance is frequently related to (i) chromosomal mutations such as those in the genes encoding the A and B subunits of the protein targets (gyrA, gyrB, parC and parE), or mutations causing reduced drug accumulation, either by a decreased uptake or by an increased efflux, and (ii) quinolone resistance genes associated with plasmids have been also described, i.e. the qnr gene that encodes a pentapeptide, which blocks the action of quinolones on the DNA gyrase and topoisomerase IV; the aac(6')-Ib-cr gene that encodes an acetylase that modifies the amino group of the piperazin ring of the fluoroquinolones and efflux pump encoded by the qepA gene that decreases intracellular drug levels.These plasmid-mediated mechanisms of resistance confer low levels of resistance but provide a favourable background in which selection of additional chromosomally encoded quinolone resistance mechanisms can occur.
Affiliation: Department of Microbiology, Hospital Clinic, School of Medicine, University of Barcelona, Barcelona, Spain.Show MeSH
Mentions: From the structural perspective, quinolones are heterocycles with a bicyclic core structure (Fig. 1). The carboxylic acid group at position 3 and the carbonyl at position 4 seem to be essential for the activity of the quinolones. In addition, bulky substituents on one face of the bicyclic core, namely at positions 1 and 7 and/or 8, are permissible and they seem to play a relevant role to determine the quinolone antibiotic spectrum. With respect to these substituents, most quinolones can be arranged into three main categories: piperazinyl‐, pyrrolidinyl‐ and piperidinyl‐type side‐chains (Hu et al., 2003). Piperazinyl‐based quinolones usually have a wide Gram‐negative coverage but a limited Gram‐positive spectrum (e.g. ciprofloxacin and levofloxacin). On the other hand, piperidinyl‐ and pyrrolidinyl‐based quinolones have a more balanced spectrum (e.g. gemifloxacin).
Affiliation: Department of Microbiology, Hospital Clinic, School of Medicine, University of Barcelona, Barcelona, Spain.