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JAC Advance Access originally published online on June 9, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(1):90-94; doi:10.1093/jac/dkh294
JAC vol.54 no.1 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.

Type II topoisomerase mutations in Bacillus anthracis associated with high-level fluoroquinolone resistance

Darrin J. Bast1,2,*, Abed Athamna3, Carla L. Duncan1, Joyce C. S. de Azavedo1,2, Donald E. Low1,2, Galia Rahav4, David Farrell5 and Ethan Rubinstein4

1 Toronto Centre for Antimicrobial Research and Evaluation (ToCARE), Room 1483, Department of Microbiology, Mount Sinai Hospital, 600 University Avenue, Toronto; 2 Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; 3 Triangle Research and Development Center, Kfar Quara, Israel; 4 The Infectious Diseases Unit, Sheba Medical Center, Tel Aviv University School of Medicine, Tel Hashomer, Israel; 5 GR Micro Ltd., London, UK

* Corresponding author. Tel: +1-416-586-3207; Fax: +1-416-586-8746; Email: dbast{at}mtsinai.on.ca

Objectives: To identify and characterize the mechanisms of high-level fluoroquinolone resistance in two strains of Bacillus anthracis following serial passage in increasing concentrations of fluoroquinolones.

Methods: Fluoroquinolone-resistant isolates of the Sterne and Russian Anthrax Vaccine STi strains were obtained following serial passage in the presence of increasing concentrations of four different fluoroquinolones. The quinolone-resistance-determining regions of the type II topoisomerase genes from the resistant strains were amplified by PCR and characterized by DNA sequence analysis. The MICs in the presence and absence of reserpine were determined using broth microdilution as a means of detecting active efflux.

Results: Single and double amino acid substitutions in the GyrA (Ser-85-Leu; Glu-89-Arg/Gly/Lys) and GrlA (Ser-81-Tyr; Val-96-Ala; Asn-70-Lys) were most common. A single amino acid substitution in GyrB (Asp-430-Asn) was also identified. Efflux only applied to isolates selected for by either levofloxacin or ofloxacin.

Conclusions: Specific amino acid substitutions in the type II topoisomerase enzymes significantly contributed to the development of high-level fluoroquinolone resistance in B. anthracis. However, notable differences between the strains and the drugs tested were identified including the role of efflux and the numbers and types of mutations identified.

Keywords: anthrax , DNA gyrase , topoisomerase IV


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