|FATEMEH, RAFII - FDA/NCTR
|PARK, M. - FDA/NCTR
Submitted to: Antimicrobial Agents and Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/25/2004
Publication Date: 2/1/2005
Citation: Fatemeh, R., Park, M., Novak, J.S. 2005. Alterations in dna gyrase and topoisomerase iv in resistant mutants of clostridium perfringens found after in vitro treatment with fluoroquinolones. Antimicrobial Agents and Chemotherapy. 49(2):488-492.
Interpretive Summary: Clostridium perfringens is one of the microorganisms recovered from some of the most serious clinical infections involving anaerobes. C. perfringens can develop resistance to a group of antibiotics called fluoroquinolones and the mechanism for acquisition of resistance requires further study. This is the first report to show a similar pattern of mutations in two specific gene regions following the acquisition of resistance to different fluoroquinolone antibiotics. The results of this study help build on the understanding of the development of resistance in pathogens, such as C. perfringens, and will aid in the development of antimicrobials to prevent this from occurring in the future, ensuring the effectiveness of treatments to combat infections and disease.
Technical Abstract: To compare mutations in the DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) genes of Clostridium perfringens, that are associated with in vitro exposure to fluoroquinolones, resistant mutants were selected from eight strains by serial passage in increasing concentrations of norfloxacin, ciprofloxacin, gatifloxacin or trovafloxacin. The nucleotide sequences of the entire gyrA, gyrB, parC and parE genes were determined for 42 mutants. Gyrase was the primary target for each fluoroquinolone and topoisomerase IV was the secondary target. Most mutations appeared in the quinolone resistance-determining regions of gyrA (resulting in changes of Asp-87 to Tyr or Gly-81 to Cys) and parC (Asp-93 or 88 to Tyr or Ser-89 to Ile); only two mutations were found in gyrB and two in parE. More multiple gyrA and parC mutants were produced with gatifloxacin than with the other fluoroquinolones tested. Allelic diversity was observed among the resistant mutants, which showed 2 to 256-fold increases in MIC. Both the structures of the drugs and their concentrations influenced the selection of mutants.