Mechanism of plasmid-mediated quinolone resistance

Abstract

Quinolones are potent antibacterial agents that specifically target bacterial DNA gyrase and topoisomerase IV. Widespread use of these agents has contributed to the rise of bacterial quinolone resistance. Previous studies have shown that quinolone resistance arises by mutations in chromosomal genes. Recently, a multiresistance plasmid was discovered that encodes transferable resistance to quinolones. We have cloned the plasmid-quinolone resistance gene, termed qnr, and found it in an integron-like environment upstream from qacE⌬1 and sulI. The gene product Qnr was a 218-aa protein belonging to the pentapeptide repeat family and shared sequence homology with the immunity protein McbG, which is thought to protect DNA gyrase from the action of microcin B17. Qnr had pentapeptide repeat domains of 11 and 28 tandem copies, separated by a single glycine with a consensus sequence of A͞C D͞N L͞F X X. Because the primary target of quinolones is DNA gyrase in Gram-negative strains, we tested the ability of Qnr to reverse the inhibition of gyrase activity by quinolones. Purified Qnr-His6 protected Escherichia coli DNA gyrase from inhibition by ciprofloxacin. Gyrase protection was proportional to the concentration of Qnr-His6 and inversely proportional to the concentration of ciprofloxacin. The protective activity of Qnr-His6 was lost by boiling the protein and involved neither quinolone inactivation nor independent gyrase activity. Protection of topoisomerase IV, a secondary target of quinolone action in E. coli, was not evident. How Qnr protects DNA gyrase and the prevalence of this resistance mechanism in clinical isolates remains to be determined.

High prevalence of plasmid-mediated quinolone resistance determinants in Enterobacter cloacae isolated from hospitals of the Qazvin, Alborz, and Tehran provinces, Iran

“…However, plasmid-mediated quinolone resistance (PMQR) has also been reported in several parts of the world (9) (10) (11) (12) (13) (14) . Plasmids carrying qnr genes widely vary in size and typically carry multiple resistance determinants (15) (16) . Qnr proteins are members of a pentapeptide repeat protein family, which is capable of protecting DNA gyrase and DNA topoisomerase IV from quinolone compounds (17) .…”

Why are bacteria refractory to antimicrobials?

“…Strains that have the vanA or vanB genes produce d-Ala-d-Lac peptidoglycan precursors that are 1000-fold less sensitive to vancomycin than the wildtype d-Ala-d-Ala form. Also, a novel plasmid-encoded protein that confers resistance to quinolone antibiotics has been discovered [4,5]. The protein protects DNA gyrase from quinolone inhibition without modifying the drug, but the protective mechanism is not known.…”

Molecular screening of antibiotic-resistant determinants among multidrug-resistant clinical isolates of <i>Proteus mirabilis</i> from SouthWest Nigeria

“…Studies have shown that they produce a low level resistance, but facilitate a higher level resistance in association with chromosomal mutations in bacteria harbouring them. 23,24,25 The aac(6')-Ib-cr, which encode a variant of aminoglycoside transferase that confers reduced susceptibility to ciprofloxacin and norfloxacin by N-acetylation of their piperazinyl amine, causes an increase in their MIC two to four fold 26 and qepA gene, which encodes quinolone-specific efflux pump 27 initiate decreased susceptibility to quinolones by up to 64-fold. 28 Resistance to aminoglycosides such as gentamicin, amikacin and tobramycin, have been attributed to the aminoglycoside-modifying enzymes.…”