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Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes

Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for six decades without significant appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance e...

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Autores principales: Evangelopoulos, Dimitrios, Prosser, Gareth A., Rodgers, Angela, Dagg, Belinda M., Khatri, Bhagwati, Ho, Mei Mei, Gutierrez, Maximiliano G., Cortes, Teresa, de Carvalho, Luiz Pedro S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744398/
https://www.ncbi.nlm.nih.gov/pubmed/31519879
http://dx.doi.org/10.1038/s41467-019-12074-z
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author Evangelopoulos, Dimitrios
Prosser, Gareth A.
Rodgers, Angela
Dagg, Belinda M.
Khatri, Bhagwati
Ho, Mei Mei
Gutierrez, Maximiliano G.
Cortes, Teresa
de Carvalho, Luiz Pedro S.
author_facet Evangelopoulos, Dimitrios
Prosser, Gareth A.
Rodgers, Angela
Dagg, Belinda M.
Khatri, Bhagwati
Ho, Mei Mei
Gutierrez, Maximiliano G.
Cortes, Teresa
de Carvalho, Luiz Pedro S.
author_sort Evangelopoulos, Dimitrios
collection PubMed
description Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for six decades without significant appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We therefore investigated why Mycobacterium tuberculosis fails to become resistant to D-cycloserine. To address this question, we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low rate of emergence of D-cycloserine resistance mutations is the dominant biological factor delaying the appearance of clinical resistance to this antibiotic. Furthermore, we also identified potential compensatory mechanisms able to minimize the severe fitness costs of primary D-cycloserine resistance conferring mutations.
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spelling pubmed-67443982019-09-16 Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes Evangelopoulos, Dimitrios Prosser, Gareth A. Rodgers, Angela Dagg, Belinda M. Khatri, Bhagwati Ho, Mei Mei Gutierrez, Maximiliano G. Cortes, Teresa de Carvalho, Luiz Pedro S. Nat Commun Article Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for six decades without significant appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We therefore investigated why Mycobacterium tuberculosis fails to become resistant to D-cycloserine. To address this question, we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low rate of emergence of D-cycloserine resistance mutations is the dominant biological factor delaying the appearance of clinical resistance to this antibiotic. Furthermore, we also identified potential compensatory mechanisms able to minimize the severe fitness costs of primary D-cycloserine resistance conferring mutations. Nature Publishing Group UK 2019-09-13 /pmc/articles/PMC6744398/ /pubmed/31519879 http://dx.doi.org/10.1038/s41467-019-12074-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Evangelopoulos, Dimitrios
Prosser, Gareth A.
Rodgers, Angela
Dagg, Belinda M.
Khatri, Bhagwati
Ho, Mei Mei
Gutierrez, Maximiliano G.
Cortes, Teresa
de Carvalho, Luiz Pedro S.
Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes
title Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes
title_full Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes
title_fullStr Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes
title_full_unstemmed Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes
title_short Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes
title_sort comparative fitness analysis of d-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744398/
https://www.ncbi.nlm.nih.gov/pubmed/31519879
http://dx.doi.org/10.1038/s41467-019-12074-z
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