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Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis

Background and objectives: Multidrug resistant (MDR) bacteria are a growing threat to global health. Studies focusing on single antibiotics have shown that drug resistance is often associated with a fitness cost in the absence of drug. However, little is known about the fitness cost associated with...

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Autores principales: Borrell, Sònia, Teo, Youjin, Giardina, Federica, Streicher, Elizabeth M., Klopper, Marisa, Feldmann, Julia, Müller, Borna, Victor, Tommie C., Gagneux, Sebastien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868377/
https://www.ncbi.nlm.nih.gov/pubmed/24481187
http://dx.doi.org/10.1093/emph/eot003
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author Borrell, Sònia
Teo, Youjin
Giardina, Federica
Streicher, Elizabeth M.
Klopper, Marisa
Feldmann, Julia
Müller, Borna
Victor, Tommie C.
Gagneux, Sebastien
author_facet Borrell, Sònia
Teo, Youjin
Giardina, Federica
Streicher, Elizabeth M.
Klopper, Marisa
Feldmann, Julia
Müller, Borna
Victor, Tommie C.
Gagneux, Sebastien
author_sort Borrell, Sònia
collection PubMed
description Background and objectives: Multidrug resistant (MDR) bacteria are a growing threat to global health. Studies focusing on single antibiotics have shown that drug resistance is often associated with a fitness cost in the absence of drug. However, little is known about the fitness cost associated with resistance to multiple antibiotics. Methodology: We used Mycobacterium smegmatis as a model for human tuberculosis (TB) and an in vitro competitive fitness assay to explore the combined fitness effects and interaction between mutations conferring resistance to rifampicin (RIF) and ofloxacin (OFX); two of the most important first- and second-line anti-TB drugs, respectively. Results: We found that 4 out of 17 M. smegmatis mutants (24%) resistant to RIF and OFX showed a statistically significantly higher or lower competitive fitness than expected when assuming a multiplicative model of fitness effects of each individual mutation. Moreover, 6 out of the 17 double drug-resistant mutants (35%) had a significantly higher fitness than at least one of the corresponding single drug-resistant mutants. The particular combinations of resistance mutations associated with no fitness deficit in M. smegmatis were the most frequent among 151 clinical isolates of MDR and extensively drug-resistant (XDR) Mycobacterium tuberculosis from South Africa. Conclusions and implications: Our results suggest that epistasis between drug resistance mutations in mycobacteria can lead to MDR strains with no fitness deficit, and that these strains are positively selected in settings with a high burden of drug-resistant TB. Taken together, our findings support a role for epistasis in the evolution and epidemiology of MDR- and XDR-TB.
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spelling pubmed-38683772014-01-06 Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis Borrell, Sònia Teo, Youjin Giardina, Federica Streicher, Elizabeth M. Klopper, Marisa Feldmann, Julia Müller, Borna Victor, Tommie C. Gagneux, Sebastien Evol Med Public Health Original Research Article Background and objectives: Multidrug resistant (MDR) bacteria are a growing threat to global health. Studies focusing on single antibiotics have shown that drug resistance is often associated with a fitness cost in the absence of drug. However, little is known about the fitness cost associated with resistance to multiple antibiotics. Methodology: We used Mycobacterium smegmatis as a model for human tuberculosis (TB) and an in vitro competitive fitness assay to explore the combined fitness effects and interaction between mutations conferring resistance to rifampicin (RIF) and ofloxacin (OFX); two of the most important first- and second-line anti-TB drugs, respectively. Results: We found that 4 out of 17 M. smegmatis mutants (24%) resistant to RIF and OFX showed a statistically significantly higher or lower competitive fitness than expected when assuming a multiplicative model of fitness effects of each individual mutation. Moreover, 6 out of the 17 double drug-resistant mutants (35%) had a significantly higher fitness than at least one of the corresponding single drug-resistant mutants. The particular combinations of resistance mutations associated with no fitness deficit in M. smegmatis were the most frequent among 151 clinical isolates of MDR and extensively drug-resistant (XDR) Mycobacterium tuberculosis from South Africa. Conclusions and implications: Our results suggest that epistasis between drug resistance mutations in mycobacteria can lead to MDR strains with no fitness deficit, and that these strains are positively selected in settings with a high burden of drug-resistant TB. Taken together, our findings support a role for epistasis in the evolution and epidemiology of MDR- and XDR-TB. Oxford University Press 2013 2013-03-08 /pmc/articles/PMC3868377/ /pubmed/24481187 http://dx.doi.org/10.1093/emph/eot003 Text en © The Author(s) 2013. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research Article
Borrell, Sònia
Teo, Youjin
Giardina, Federica
Streicher, Elizabeth M.
Klopper, Marisa
Feldmann, Julia
Müller, Borna
Victor, Tommie C.
Gagneux, Sebastien
Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis
title Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis
title_full Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis
title_fullStr Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis
title_full_unstemmed Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis
title_short Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis
title_sort epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868377/
https://www.ncbi.nlm.nih.gov/pubmed/24481187
http://dx.doi.org/10.1093/emph/eot003
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