Plasmid-mediated quinolone resistance: a multifaceted threat

Abstract

Although plasmid-mediated quinolone resistance (PMQR) was thought not to exist before its discovery in 1998, the past decade has seen an explosion of research characterizing this phenomenon. The best-described form of PMQR is determined by the qnr group of genes. These genes, likely originating in aquatic organisms, code for pentapeptide repeat proteins. These proteins reduce susceptibility to quinolones by protecting the complex of DNA and DNA gyrase or topoisomerase IV enzymes from the inhibitory effect of quinolones. Two additional PMQR mechanisms were recently described. aac(6')-Ib-cr encodes a variant aminoglycoside acetyltransferase with two amino acid alterations allowing it to inactivate ciprofloxacin through the acetylation of its piperazinyl substituent. oqxAB and qepA encode efflux pumps that extrude quinolones. All of these genes determine relatively small increases in the MICs of quinolones, but these changes are sufficient to facilitate the selection of mutants with higher levels of resistance. The contribution of these genes to the emergence of quinolone resistance is being actively investigated. Several factors suggest their importance in this process, including their increasing ubiquity, their association with other resistance elements, and their emergence simultaneous with the expansion of clinical quinolone resistance. Of concern, these genes are not yet being taken into account in resistance screening by clinical microbiology laboratories.

FIG. 1.

Amino acid sequence of Qnr displayed to emphasize the pentapeptide repeating unit with a consensus sequence of S/T/A/V/C-D/N-L/F-S/T/R-G. (A) QnrA1. (B) QnrB1. (C) QnrS1. (D) QnrC. (E) QnrD. No QnrC or QnrD variants have been described yet; yellow highlighting indicates the pentapeptide repeat according to Pfam website platform analysis; boldface type indicates residues that conform to the pentapeptide amino acid motif; boxed areas are amino acid changes in some Qnr variants.

FIG. 2.

MPC assay. About 10¹⁰ organisms and appropriate dilutions were applied onto Mueller-Hinton agar plates containing the indicated concentrations of ciprofloxacin. Surviving colonies were counted after incubation for 72 h at 37°C. The lowest concentration of ciprofloxacin at which no mutant colonies were seen was 0.2 μg/ml for J53 and 3.2 μg/ml for J53 pBC SK-aac(6′)Ib-cr or J53 pBC SK-qnrA1. (Reprinted from reference with permission from Elsevier.)

FIG. 3.

Genetic environment of plasmid-determined qnrA, qnrB, and qnrS alleles. See Table 2 for references.