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Impact of Amino Acid Substitutions in B Subunit of DNA Gyrase in Mycobacterium leprae on Fluoroquinolone Resistance

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Title: Impact of Amino Acid Substitutions in B Subunit of DNA Gyrase in Mycobacterium leprae on Fluoroquinolone Resistance
Authors: Yokoyama, Kazumasa Browse this author
Kim, Hyun Browse this author
Mukai, Tetsu Browse this author
Matsuoka, Masanori Browse this author
Nakajima, Chie Browse this author →KAKEN DB
Suzuki, Yasuhiko Browse this author →KAKEN DB
Issue Date: 11-Oct-2012
Publisher: Public Library of Science
Journal Title: PLoS Neglected Tropical Diseases
Volume: 6
Issue: 10
Start Page: e1838
Publisher DOI: 10.1371/journal.pntd.0001838
Abstract: Background: Ofloxacin is a fluoroquinolone (FQ) used for the treatment of leprosy. FQs are known to interact with both A and B subunits of DNA gyrase and inhibit supercoiling activity of this enzyme. Mutations conferring FQ resistance have been reported to be found only in the gene encoding A subunit of this enzyme (gyrA) of M. leprae, although there are many reports on the FQ resistance-associated mutation in gyrB in other bacteria, including M. tuberculosis, a bacterial species in the same genus as M. leprae. Methodology/Principal Findings: To reveal the possible contribution of mutations in gyrB to FQ resistance in M. leprae, we examined the inhibitory activity of FQs against recombinant DNA gyrases with amino acid substitutions at position 464, 502 and 504, equivalent to position 461, 499 and 501 in M. tuberculosis, which are reported to contribute to reduced sensitivity to FQ. The FQ-inhibited supercoiling assay and FQ-induced cleavage assay demonstrated the important roles of these amino acid substitutions in reduced sensitivity to FQ with marked influence by amino acid substitution, especially at position 502. Additionally, effectiveness of sitafloxacin, a FQ, to mutant DNA gyrases was revealed by low inhibitory concentration of this FQ. Significance: Data obtained in this study suggested the possible emergence of FQ-resistant M. leprae with mutations in gyrB and the necessity of analyzing both gyrA and gyrB for an FQ susceptibility test. In addition, potential use of sitafloxacin for the treatment of problematic cases of leprosy by FQ resistant M. leprae was suggested.
Type: article
Appears in Collections:人獣共通感染症国際共同研究所 (International Institute for Zoonosis Control) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 鈴木 定彦

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