Emergence of phenotypic and genotypic antimicrobial resistance in Mycobacterium tuberculosis

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 experimen...

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Published in:Scientific reports 2022-12, Vol.12 (1), p.21429-21429, Article 21429
Main Authors: Kloprogge, Frank, Ortiz Canseco, Julio, Phee, Lynette, Sadouki, Zahra, Kipper, Karin, Witney, Adam A., Stoker, Neil, McHugh, Timothy D.
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Language:English
Subjects:
692/308
692/308/153
Anti-Bacterial Agents
Antibiotics
Antimicrobial agents
Antimicrobial resistance
Bacteria
Clinical trials
Drug development
Drug dosages
Drug resistance
Drug Resistance, Bacterial - genetics
Genotype
Granuloma
HIV
Human immunodeficiency virus
Humanities and Social Sciences
Infections
Isoniazid
Isoniazid - pharmacology
multidisciplinary
Mycobacterium tuberculosis - genetics
Pharmacodynamics
Rifampin
Rifampin - pharmacology
Science
Science (multidisciplinary)
Tuberculosis
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container_title Scientific reports
container_volume 12
creator Kloprogge, Frank
Ortiz Canseco, Julio
Phee, Lynette
Sadouki, Zahra
Kipper, Karin
Witney, Adam A.
Stoker, Neil
McHugh, Timothy D.
description 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.
doi_str_mv 10.1038/s41598-022-25827-6
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subjects 692/308
692/308/153
Anti-Bacterial Agents
Antibiotics
Antimicrobial agents
Antimicrobial resistance
Bacteria
Clinical trials
Drug development
Drug dosages
Drug resistance
Drug Resistance, Bacterial - genetics
Genotype
Granuloma
HIV
Human immunodeficiency virus
Humanities and Social Sciences
Infections
Isoniazid
Isoniazid - pharmacology
multidisciplinary
Mycobacterium tuberculosis - genetics
Pharmacodynamics
Rifampin
Rifampin - pharmacology
Science
Science (multidisciplinary)
Tuberculosis
title Emergence of phenotypic and genotypic antimicrobial resistance in Mycobacterium tuberculosis
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