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Emergence of phenotypic and genotypic antimicrobial resistance in Mycobacterium tuberculosis

Kloprogge, F; Ortiz Canseco, J; Phee, L; Sadouki, Z; Kipper, K; Witney, AA; Stoker, N; (2022) Emergence of phenotypic and genotypic antimicrobial resistance in Mycobacterium tuberculosis. Scientific Reports , 12 , Article 21429. 10.1038/s41598-022-25827-6. Green open access

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Abstract

Concentration dependency of phenotypic and genotypic isoniazid-rifampicin resistance emergence was investigated to obtain a mechanistic understanding on how anti-mycobacterial drugs facilitate the emergence of bacterial populations that survive throughout treatment. Using static kill curve experiments, observing two evolution cycles, it was demonstrated that rifampicin resistance was the result of non-specific mechanisms and not associated with accumulation of drug resistance encoding SNPs. Whereas, part of isoniazid resistance could be accounted for by accumulation of specific SNPs, which was concentration dependent. Using a Hollow Fibre Infection Model it was demonstrated that emergence of resistance did not occur at concentration–time profiles mimicking the granuloma. This study showed that disentangling and quantifying concentration dependent emergence of resistance provides an improved rational for drug and dose selection although further work to understand the underlying mechanisms is needed to improve the drug development pipeline.

Type: Article
Title: Emergence of phenotypic and genotypic antimicrobial resistance in Mycobacterium tuberculosis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41598-022-25827-6
Publisher version: https://doi.org/10.1038/s41598-022-25827-6
Language: English
Additional information: 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords: Mycobacterium tuberculosis, Anti-Bacterial Agents, Drug Resistance, Bacterial, Genotype, Isoniazid, Rifampin
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health
URI: https://discovery.ucl.ac.uk/id/eprint/10162178
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