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Quinolone resistance and CF

Despite the wide variety of antibiotics available, with their multiple methods of action, resistance to antibiotics is a serious public health issue. Cystic Fibrosis (CF) patients represent a cohort who are dependent on effective antibiotic treatment. Quinolones are an example of a broad spectrum antibiotic class used widely in treatment of infections in CF patients as well as in other groups.

Quinolone antibiotics target both DNA gyrase, composed of the subunits GyrA and GyrB and DNA topoisomerase IV, composed of ParC and ParE. Many pathogenic bacteria including Pseudomonas aeruginosa have developed resistance to quinolones due to the widespread use of these antibiotics. Pseudomonas aeruginosa, a Gram-negative bacterium, is a major pathogen of CF patients and a significant cause of death in these patients.

Studies on clinical samples have addressed the major mechanisms of resistance to quinolones and have identified mutations in the gyrA gene as being the most common, most importantly at the highly conserved position 83 of GyrA (serine or threonine). Mutations in GyrB and ParE have also been shown to contribute to resistance. Interestingly however, in terms of CF, a review from the University of Ottowa comparing resistance to quinolones between samples from CF patients and those from non-CF patients with acute infections revealed some differences in non-gyrase resistance-conferring mutations. These focused on genes encoding pumps responsible for influx or efflux of drugs and can therefore affect the intracellular concentration of drugs including quinolones. In terms of Pseudomonas aeruginosa, two efflux pumps, MexAB-OprM and MexCD-OprJ are implicated in quinolone resistance. Genes named mexR and nfxB respectively encode repressors of these two pumps. The review revealed that in CF samples mutations of nfxB were present in 57% of samples; none carried mutations in mexR or in the topoisomerase gene parC. However, nfxB mutations were relatively uncommon in non-CF samples, while parC and mexR mutations were found in 48% and 33% of cases respectively. This suggests that environment-specific mechanisms are at work in Pseudomonas aeruginosa quinolone resistance, for example related to biofilm growth in CF patients, effective drug does or epistasis. Thus local environmental differences in mechanisms of drug resistance need to be considered in devising choice of drug treatment in CF and other diseases.

Sources

WONG, A. and KASSEN, R., 2011. Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa. Microbiology (Reading, England), 157, pp. 937-944

WONG, A., RODRIGUE, N. and KASSEN, R., 2012. Genomics of adaptation during experimental evolution of the opportunistic pathogen Pseudomonas aeruginosa. Plos Genetics, 8(9), pp. e1002928-e1002928

MAEDA, Y. et al., 2011. Molecular characterization and phylogenetic analysis of quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC and parE gene loci in viridans group streptococci isolated from adult patients with cystic fibrosis. The Journal of antimicrobial chemotherapy, 66(3), pp. 476-486