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

 

Show simple item record

dc.contributor.author Klopper, Marisa
dc.contributor.author Heupink, Tim H
dc.contributor.author Hill-Cawthorne, Grant
dc.contributor.author Streicher, Elizabeth M
dc.contributor.author Dippenaar, Anzaan
dc.contributor.author de Vos, Margaretha
dc.contributor.author Abdallah, Abdallah M
dc.contributor.author Limberis, Jason
dc.contributor.author Merker, Matthias
dc.contributor.author Burns, Scott
dc.contributor.author Niemann, Stefan
dc.contributor.author Dheda, Keertan
dc.contributor.author Posey, James
dc.contributor.author Pain, Arnab
dc.contributor.author Warren, Robin M
dc.date.accessioned 2020-03-02T12:16:36Z
dc.date.available 2020-03-02T12:16:36Z
dc.date.issued 2020-02-21
dc.identifier.citation BMC Medicine. 2020 Feb 21;18(1):24
dc.identifier.uri https://doi.org/10.1186/s12916-019-1487-2
dc.identifier.uri http://hdl.handle.net/11427/31442
dc.description.abstract 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.
dc.subject Tuberculosis
dc.subject Drug-resistant
dc.subject Beyond-XDR-TB
dc.subject Missed resistance
dc.subject Weakened regimen
dc.subject Whole genome sequencing
dc.subject Atypical Beijing
dc.subject Bedaquiline
dc.title A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic
dc.type Journal Article
dc.date.updated 2020-02-23T04:31:46Z
dc.language.rfc3066 en
dc.rights.holder The Author(s).
dc.identifier.apacitation Klopper, M., Heupink, T. H., Hill-Cawthorne, G., Streicher, E. M., Dippenaar, A., de Vos, M., ... Warren, R. M. (2020). A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic. http://hdl.handle.net/11427/31442 en_ZA
dc.identifier.chicagocitation Klopper, Marisa, Tim H Heupink, Grant Hill-Cawthorne, Elizabeth M Streicher, Anzaan Dippenaar, Margaretha de Vos, Abdallah M Abdallah, et al "A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic." (2020) http://hdl.handle.net/11427/31442 en_ZA
dc.identifier.vancouvercitation Klopper M, Heupink TH, Hill-Cawthorne G, Streicher EM, Dippenaar A, de Vos M, et al. A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic. 2020; http://hdl.handle.net/11427/31442. en_ZA
dc.identifier.ris TY - Journal Article AU - Klopper, Marisa AU - Heupink, Tim H AU - Hill-Cawthorne, Grant AU - Streicher, Elizabeth M AU - Dippenaar, Anzaan AU - de Vos, Margaretha AU - Abdallah, Abdallah M AU - Limberis, Jason AU - Merker, Matthias AU - Burns, Scott AU - Niemann, Stefan AU - Dheda, Keertan AU - Posey, James AU - Pain, Arnab AU - Warren, Robin M AB - 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. DA - 2020-02-21 DB - OpenUCT DP - University of Cape Town KW - Tuberculosis KW - Drug-resistant KW - Beyond-XDR-TB KW - Missed resistance KW - Weakened regimen KW - Whole genome sequencing KW - Atypical Beijing KW - Bedaquiline LK - https://open.uct.ac.za PY - 2020 T1 - A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic TI - A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic UR - http://hdl.handle.net/11427/31442 ER - en_ZA


Files in this item

This item appears in the following Collection(s)

Show simple item record