Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance.
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 subuni...
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ftdoajarticles:oai:doaj.org/article:cdaf8f9f085444d28773a31af407c250 2023-05-15T15:13:02+02:00 Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. Kazumasa Yokoyama Hyun Kim Tetsu Mukai Masanori Matsuoka Chie Nakajima Yasuhiko Suzuki 2012-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0001838 https://doaj.org/article/cdaf8f9f085444d28773a31af407c250 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3469482?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 doi:10.1371/journal.pntd.0001838 1935-2727 1935-2735 https://doaj.org/article/cdaf8f9f085444d28773a31af407c250 PLoS Neglected Tropical Diseases, Vol 6, Iss 10, p e1838 (2012) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2012 ftdoajarticles https://doi.org/10.1371/journal.pntd.0001838 2022-12-31T11:35:22Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 6 10 e1838 |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Kazumasa Yokoyama Hyun Kim Tetsu Mukai Masanori Matsuoka Chie Nakajima Yasuhiko Suzuki Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Kazumasa Yokoyama Hyun Kim Tetsu Mukai Masanori Matsuoka Chie Nakajima Yasuhiko Suzuki |
author_facet |
Kazumasa Yokoyama Hyun Kim Tetsu Mukai Masanori Matsuoka Chie Nakajima Yasuhiko Suzuki |
author_sort |
Kazumasa Yokoyama |
title |
Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. |
title_short |
Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. |
title_full |
Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. |
title_fullStr |
Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. |
title_full_unstemmed |
Impact of amino acid substitutions in B subunit of DNA gyrase in Mycobacterium leprae on fluoroquinolone resistance. |
title_sort |
impact of amino acid substitutions in b subunit of dna gyrase in mycobacterium leprae on fluoroquinolone resistance. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2012 |
url |
https://doi.org/10.1371/journal.pntd.0001838 https://doaj.org/article/cdaf8f9f085444d28773a31af407c250 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 6, Iss 10, p e1838 (2012) |
op_relation |
http://europepmc.org/articles/PMC3469482?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 doi:10.1371/journal.pntd.0001838 1935-2727 1935-2735 https://doaj.org/article/cdaf8f9f085444d28773a31af407c250 |
op_doi |
https://doi.org/10.1371/journal.pntd.0001838 |
container_title |
PLoS Neglected Tropical Diseases |
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6 |
container_issue |
10 |
container_start_page |
e1838 |
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1766343631556313088 |