A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic
Date
2020-02-04
Journal Title
Journal ISSN
Volume Title
Publisher
BMC (part of Springer Nature)
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.
Description
CITATION: Klopper, M., et al. 2020. A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic. BMC Medicine, 18:24, doi:10.1186/s12916-019-1487-2.
The original publication is available at https://bmcmedicine.biomedcentral.com
The original publication is available at https://bmcmedicine.biomedcentral.com
Keywords
Tuberculosis -- Epidemiology, Multidrug-resistant tuberculosis -- Epidemiology, Genomics -- Research
Citation
Klopper, M., et al. 2020. A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic. BMC Medicine, 18:24, doi:10.1186/s12916-019-1487-2