UZH-Logo

Maintenance Infos

Directed mutagenesis of Mycobacterium smegmatis 16S rRNA to reconstruct the in-vivo evolution of aminoglycoside resistance in Mycobacterium tuberculosis


Shcherbakov, D; Akbergenov, R; Mattina, T; Sander, P; Andersson, D I; Böttger, E C (2010). Directed mutagenesis of Mycobacterium smegmatis 16S rRNA to reconstruct the in-vivo evolution of aminoglycoside resistance in Mycobacterium tuberculosis. Molecular Microbiology, 77(4):830-840.

Abstract

Summary Drug resistance in Mycobacteriumtuberculosis is a global problem, with major consequences for treatment and public health systems. As the emergence and spread of drug-resistant tuberculosis epidemics is largely influenced by the impact of the resistance mechanism on bacterial fitness, we wished to investigate whether compensatory evolution occurs in drug resistant clinical isolates of M. tuberculosis. By combining information from molecular epidemiology studies of drug resistant clinical M. tuberculosis isolates with genetic reconstructions and measurements of aminoglycoside susceptibility and fitness in M. smegmatis, we have reconstructed a plausible pathway for how aminoglycoside resistance develops in clinical isolates of M. tuberculosis. Thus, we show by reconstruction experiments that base changes in the highly conserved A-site of 16S rRNA that (i) cause aminoglycoside resistance, (ii) confer a high fitness cost and (iii) destabilize a stem-loop structure, are associated with a particular compensatory point mutation that restores rRNA secondary structure and bacterial fitness, while maintaining to a large extent the drug resistant phenotype. The same types of resistance and associated mutations can be found in M. tuberculosis in clinical isolates, suggesting that compensatory evolution contributes to the spread of drug-resistant tuberculosis disease.

Summary Drug resistance in Mycobacteriumtuberculosis is a global problem, with major consequences for treatment and public health systems. As the emergence and spread of drug-resistant tuberculosis epidemics is largely influenced by the impact of the resistance mechanism on bacterial fitness, we wished to investigate whether compensatory evolution occurs in drug resistant clinical isolates of M. tuberculosis. By combining information from molecular epidemiology studies of drug resistant clinical M. tuberculosis isolates with genetic reconstructions and measurements of aminoglycoside susceptibility and fitness in M. smegmatis, we have reconstructed a plausible pathway for how aminoglycoside resistance develops in clinical isolates of M. tuberculosis. Thus, we show by reconstruction experiments that base changes in the highly conserved A-site of 16S rRNA that (i) cause aminoglycoside resistance, (ii) confer a high fitness cost and (iii) destabilize a stem-loop structure, are associated with a particular compensatory point mutation that restores rRNA secondary structure and bacterial fitness, while maintaining to a large extent the drug resistant phenotype. The same types of resistance and associated mutations can be found in M. tuberculosis in clinical isolates, suggesting that compensatory evolution contributes to the spread of drug-resistant tuberculosis disease.

Citations

45 citations in Web of Science®
52 citations in Scopus®
Google Scholar™

Altmetrics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Microbiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:18 Jan 2011 12:37
Last Modified:05 Apr 2016 14:27
Publisher:Wiley-Blackwell
ISSN:0950-382X
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/j.1365-2958.2010.07218.x
PubMed ID:20545852

Download

Full text not available from this repository.View at publisher

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations