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Published in: BMC Medicine 1/2020

01-12-2020 | Tuberculosis | Research article

A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic

Authors: Marisa Klopper, Tim Hermanus Heupink, Grant Hill-Cawthorne, Elizabeth Maria Streicher, Anzaan Dippenaar, Margaretha de Vos, Abdallah Musa Abdallah, Jason Limberis, Matthias Merker, Scott Burns, Stefan Niemann, Keertan Dheda, James Posey, Arnab Pain, Robin Mark Warren

Published in: BMC Medicine | Issue 1/2020

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Abstract

Background

Atypical Beijing genotype Mycobacterium tuberculosis strains are widespread in South Africa and have acquired resistance to up to 13 drugs on multiple occasions. It is puzzling that these strains have retained fitness and transmissibility despite the potential fitness cost associated with drug resistance mutations.

Methods

We conducted Illumina sequencing of 211 Beijing genotype M. tuberculosis isolates to facilitate the detection of genomic features that may promote acquisition of drug resistance and restore fitness in highly resistant atypical Beijing forms. Phylogenetic and comparative genomic analysis was done to determine changes that are unique to the resistant strains that also transmit well. Minimum inhibitory concentration (MIC) determination for streptomycin and bedaquiline was done for a limited number of isolates to demonstrate a difference in MIC between isolates with and without certain variants.

Results

Phylogenetic analysis confirmed that two clades of atypical Beijing strains have independently developed resistance to virtually all the potent drugs included in standard (pre-bedaquiline) drug-resistant TB treatment regimens. We show that undetected drug resistance in a progenitor strain was likely instrumental in this resistance acquisition. In this cohort, ethionamide (ethA A381P) resistance would be missed in first-line drug-susceptible isolates, and streptomycin (gidB L79S) resistance may be missed due to an MIC close to the critical concentration. Subsequent inadequate treatment historically led to amplification of resistance and facilitated spread of the strains. Bedaquiline resistance was found in a small number of isolates, despite lack of exposure to the drug. The highly resistant clades also carry inhA promoter mutations, which arose after ethA and katG mutations. In these isolates, inhA promoter mutations do not alter drug resistance, suggesting a possible alternative role.

Conclusion

The presence of the ethA mutation in otherwise susceptible isolates from ethionamide-naïve patients demonstrates that known exposure is not an adequate indicator of drug susceptibility. Similarly, it is demonstrated that bedaquiline resistance can occur without exposure to the drug. Inappropriate treatment regimens, due to missed resistance, leads to amplification of resistance, and transmission. We put these results into the context of current WHO treatment regimens, underscoring the risks of treatment without knowledge of the full drug resistance profile.
Appendix
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Metadata
Title
A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic
Authors
Marisa Klopper
Tim Hermanus Heupink
Grant Hill-Cawthorne
Elizabeth Maria Streicher
Anzaan Dippenaar
Margaretha de Vos
Abdallah Musa Abdallah
Jason Limberis
Matthias Merker
Scott Burns
Stefan Niemann
Keertan Dheda
James Posey
Arnab Pain
Robin Mark Warren
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2020
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-019-1487-2

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