Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa

Abstract

The emergence and spread of antibiotic resistance in pathogens is a major impediment to the control of microbial disease. Here, we review mechanisms of quinolone resistance in Pseudomonas aeruginosa, an important nosocomial pathogen and a major cause of morbidity in cystic fibrosis (CF) patients. In this quantitative literature review, we find that mutations in DNA gyrase A, the primary target of quinolones in Gram-negative bacteria, are the most common resistance mutations identified in clinical samples of all origins, in keeping with previous observations. However, the identities of non-gyrase resistance mutations vary systematically between samples isolated from CF patients and those isolated from acute infections. CF-derived strains tend to harbour mutations in the efflux pump regulator nfxB, while non-CF strains tend to bear mutations in the efflux regulator mexR or in parC, which encodes one of two subunits of DNA topoisomerase IV. We suggest that differences in resistance mechanisms between CF and non-CF strains result either from local adaptation to different sites of infection or from differences in mutational processes between different environments. We further discuss the therapeutic implications of local differentiation in resistance mechanisms to a common antibiotic.

Quantitative Contributions of Target Alteration and Decreased Drug Accumulation to Pseudomonas aeruginosa Fluoroquinolone Resistance

“…It has been observed before that highly resistant P. aeruginosa isolates harboring a double gyrA and parC mutation are isolated almost exclusively from non-CF patients, whereas in isolates from CF patients, single mutations within the QRDRs dominate (34,35,36). Interestingly, in accordance with the previous reports, 27 of the 29 gyrA parC mutants in this study were isolated from non-CF patients.…”

Cost of Adaptation and Fitness Effects of Beneficial Mutations inPseudomonas fluorescens

“…As is often observed in clinical strains of Gram-negative bacteria resistant to quinolones, all but three strains contained mutations in the QRDR of gyrA. Within this site we found five distinct mutations, four of which occur at two amino acid sites (83 and 87) known to be associated with binding of GyrA to DNA (Wong and Kassen 2011). No further mutations were found at the sites often associated with the primary incidences of quinolone resistance-gyrB, parC, or parE-among the subset of the top 18 chosen for further sequencing.…”

“…The observation of double mutants is not unusual, at least among clinical isolates of P. aeruginosa. Wong and Kassen (2011) showed that clinical isolates of fluoroquinolone-resistant P. aeruginosa often contain multiple mutations to both gyrases and efflux pumps and that the identity of the efflux pump mutation depends on whether the infection is acute or chronic. Although it is unlikely that double mutants arise simultaneously in clinical strains, the fact that they do happen at all suggests that having more than one resistanceassociated mutation confers a fitness advantage.…”

“…Although we have not undertaken an exhaustive analysis to identify all possible sites conferring resistance in our collection, we have found five distinct nonsynonymous mutations in 15 of the 18 strains sequenced from a 500-bp region of the QRDR of gyrA (Table 1). Four mutations are substitutions in either amino acids 83 (Thr) or 87 (Asp), which are among the most common sites associated with resistance to quinolones in clinical isolates of Pseudomonas aeruginosa (Wong and Kassen 2011), and one is at position 81 (Gly). Additional sequencing and phenotypic assays (see below and Table 1) reveal at least 15 unique genotypes in our top 18 collection.…”

Plasmid Mediated Quinolone Resistance Determinants among Nosocomial Clinical Pseudomonas aeruginosa Isolates

“…Antibiotic resistance is a significant and mounting hurdle to the treatment and management of microbial disease (Wong and Kassen, 2011). The subsequent increase in quinolone resistance is currently undermining the clinical utility for various infections (Kim and Hooper, 2014).In particular, resistant P. aeruginosa infections are associated with adverse outcomes such as high mortality, morbidity, and expanded costs (Nathwaniet al, 2014).…”