Mechanism of action of and resistance to quinolones

Abstract

SummaryFluoroquinolones are an important class of wide‐spectrum antibacterial agents. The first quinolone described was nalidixic acid, which showed a narrow spectrum of activity. 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. Quinolones inhibit DNA gyrase and topoisomerase IV activities, two enzymes essential for bacteria viability. 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.

Temporal Interplay between Efflux Pumps and Target Mutations in Development of Antibiotic Resistance in Escherichia coli

“…However, multiple studies showed that gyrB and parE were not common target sites for mutation in Gram-negative pathogens (2,11,30,40) and that gyrA mutation was the most common first mutational step in quinolone resistance. The in vitro model utilized in our studies also could not mimic in vivo conditions, such as the pathology of infection, host-defense mechanisms, virulence, and metabolic behavior of the pathogen.…”

Constitutive SoxS Expression in a Fluoroquinolone-Resistant Strain with a Truncated SoxR Protein and Identification of a New Member of themarA-soxS-robRegulon,mdtG

“…They result from both chromosomally encoded mutations and plasmid-mediated quinolone resistance (10). The first mechanism includes mutations of the target genes gyrA and gyrB, which encode DNA gyrase, and parC and parE, encoding topoisomerase IV (29,35,41,43,44), as well as mutations responsible for a decrease in quinolone permeability, either by increasing the efflux or by decreasing the expression of outer membrane proteins used as entrance channels (5,7,9,34).…”

Biological evaluation and molecular modelling study of thiosemicarbazide derivatives as bacterial type IIA topoisomerases inhibitors

“…Gyrase is primarily responsible for introducing negative supercoils into conformationally constrained DNA, while topoisomerase IV primarily resolves linked chromosome dimers at the conclusion of DNA replication [14][15][16][17] . Inhibitors of DNA gyrase typically also inhibit bacterial topoisomerase IV, although the relative importance for expression of antibacterial activity can vary depending on the inhibitor and the bacterial species [18][19][20] . Recently 21 , we showed for the first time inhibitory potency of two 4-benzoylthiosemicarbazides towards bacterial topoisomerase IV ( Figure 1).…”