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Resistance of M. leprae to Quinolones: A Question of Relativity?
Multidrug resistant leprosy, defined as resistance to rifampin, dapsone and fluoroquinolones (FQ), has been described in Mycobacterium leprae. However, the in vivo impact of fluoroquinolone resistance, mainly mediated by mutations in DNA gyrase (GyrA(2)GyrB(2)), has not been precisely assessed. Our...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828155/ https://www.ncbi.nlm.nih.gov/pubmed/24244784 http://dx.doi.org/10.1371/journal.pntd.0002559 |
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author | Veziris, Nicolas Chauffour, Aurélie Escolano, Sylvie Henquet, Sarah Matsuoka, Masanori Jarlier, Vincent Aubry, Alexandra |
author_facet | Veziris, Nicolas Chauffour, Aurélie Escolano, Sylvie Henquet, Sarah Matsuoka, Masanori Jarlier, Vincent Aubry, Alexandra |
author_sort | Veziris, Nicolas |
collection | PubMed |
description | Multidrug resistant leprosy, defined as resistance to rifampin, dapsone and fluoroquinolones (FQ), has been described in Mycobacterium leprae. However, the in vivo impact of fluoroquinolone resistance, mainly mediated by mutations in DNA gyrase (GyrA(2)GyrB(2)), has not been precisely assessed. Our objective was to measure the impact of a DNA gyrase mutation whose implication in fluoroquinolone resistance has been previously demonstrated through biochemical studies, on the in vivo activity of 3 fluoroquinolones: ofloxacin, moxifloxacin and garenoxacin. METHODOLOGY/PRINCIPAL FINDINGS: We used the proportional bactericidal method. 210 four-week-old immunodeficient female Nude mice (NMRI-Foxn1(nu)/Foxn1(nu)) were inoculated in the left hind footpad with 0.03 ml of bacterial suspension containing 5×10(3), 5×10(2), 5×10(1), and 5×10(0) M. leprae AFB organisms of strain Hoshizuka-4 which is a multidrug resistant strain harboring a GyrA A91V substitution. An additional subgroup of 10 mice was inoculated with 5×10(−1) bacilli in the untreated control group. The day after inoculation, subgroups of mice were treated with a single dose of ofloxacin, moxifloxacin, garenoxacin or clarithromycin at 150 mg/kg dosing. 12 months later mice were sacrificed and M. leprae bacilli were numbered in the footpad. The results from the untreated control group indicated that the infective inoculum contained 23% of viable M. leprae. The results from the moxifloxacin and garenoxacin groups indicated that a single dose of these drugs reduced the percentage of viable M. leprae by 90%, similarly to the reduction observed after a single dose of the positive control drug clarithromycin. Conversely, ofloxacin was less active than clarithromycin. CONCLUSION/SIGNIFICANCE: DNA gyrase mutation is not always synonymous of lack of in vivo fluoroquinolone activity in M. leprae. As for M. tuberculosis, in vivo studies allow to measure residual antibiotic activity in case of target mutations in M. leprae. |
format | Online Article Text |
id | pubmed-3828155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38281552013-11-16 Resistance of M. leprae to Quinolones: A Question of Relativity? Veziris, Nicolas Chauffour, Aurélie Escolano, Sylvie Henquet, Sarah Matsuoka, Masanori Jarlier, Vincent Aubry, Alexandra PLoS Negl Trop Dis Research Article Multidrug resistant leprosy, defined as resistance to rifampin, dapsone and fluoroquinolones (FQ), has been described in Mycobacterium leprae. However, the in vivo impact of fluoroquinolone resistance, mainly mediated by mutations in DNA gyrase (GyrA(2)GyrB(2)), has not been precisely assessed. Our objective was to measure the impact of a DNA gyrase mutation whose implication in fluoroquinolone resistance has been previously demonstrated through biochemical studies, on the in vivo activity of 3 fluoroquinolones: ofloxacin, moxifloxacin and garenoxacin. METHODOLOGY/PRINCIPAL FINDINGS: We used the proportional bactericidal method. 210 four-week-old immunodeficient female Nude mice (NMRI-Foxn1(nu)/Foxn1(nu)) were inoculated in the left hind footpad with 0.03 ml of bacterial suspension containing 5×10(3), 5×10(2), 5×10(1), and 5×10(0) M. leprae AFB organisms of strain Hoshizuka-4 which is a multidrug resistant strain harboring a GyrA A91V substitution. An additional subgroup of 10 mice was inoculated with 5×10(−1) bacilli in the untreated control group. The day after inoculation, subgroups of mice were treated with a single dose of ofloxacin, moxifloxacin, garenoxacin or clarithromycin at 150 mg/kg dosing. 12 months later mice were sacrificed and M. leprae bacilli were numbered in the footpad. The results from the untreated control group indicated that the infective inoculum contained 23% of viable M. leprae. The results from the moxifloxacin and garenoxacin groups indicated that a single dose of these drugs reduced the percentage of viable M. leprae by 90%, similarly to the reduction observed after a single dose of the positive control drug clarithromycin. Conversely, ofloxacin was less active than clarithromycin. CONCLUSION/SIGNIFICANCE: DNA gyrase mutation is not always synonymous of lack of in vivo fluoroquinolone activity in M. leprae. As for M. tuberculosis, in vivo studies allow to measure residual antibiotic activity in case of target mutations in M. leprae. Public Library of Science 2013-11-14 /pmc/articles/PMC3828155/ /pubmed/24244784 http://dx.doi.org/10.1371/journal.pntd.0002559 Text en © 2013 Veziris et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Veziris, Nicolas Chauffour, Aurélie Escolano, Sylvie Henquet, Sarah Matsuoka, Masanori Jarlier, Vincent Aubry, Alexandra Resistance of M. leprae to Quinolones: A Question of Relativity? |
title | Resistance of M. leprae to Quinolones: A Question of Relativity? |
title_full | Resistance of M. leprae to Quinolones: A Question of Relativity? |
title_fullStr | Resistance of M. leprae to Quinolones: A Question of Relativity? |
title_full_unstemmed | Resistance of M. leprae to Quinolones: A Question of Relativity? |
title_short | Resistance of M. leprae to Quinolones: A Question of Relativity? |
title_sort | resistance of m. leprae to quinolones: a question of relativity? |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828155/ https://www.ncbi.nlm.nih.gov/pubmed/24244784 http://dx.doi.org/10.1371/journal.pntd.0002559 |
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