A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic
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 associ...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-02-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12916-019-1487-2 |
| _version_ | 1830284358523551744 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Marisa Klopper |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T03:17:00Z |
| format | Article |
| id | doaj.art-94b53d5408b144e69d8124dbfc6439ad |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-12-19T03:17:00Z |
| publishDate | 2020-02-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-94b53d5408b144e69d8124dbfc6439ad2022-12-21T20:37:51ZengBMCBMC Medicine1741-70152020-02-0118111410.1186/s12916-019-1487-2A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemicMarisa Klopper0Tim Hermanus Heupink1Grant Hill-Cawthorne2Elizabeth Maria Streicher3Anzaan Dippenaar4Margaretha de Vos5Abdallah Musa Abdallah6Jason Limberis7Matthias Merker8Scott Burns9Stefan Niemann10Keertan Dheda11James Posey12Arnab Pain13Robin Mark Warren14South African Medical Research Council Centre for Tuberculosis Research, DST NRF Centre of Excellence for Biomedical Tuberculosis research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch UniversityGlobal Health Institute, Epidemiology and Social Medicine, University of AntwerpSydney School of Public Health, Faculty of Medicine and Health, University of SydneySouth African Medical Research Council Centre for Tuberculosis Research, DST NRF Centre of Excellence for Biomedical Tuberculosis research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch UniversitySouth African Medical Research Council Centre for Tuberculosis Research, DST NRF Centre of Excellence for Biomedical Tuberculosis research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch UniversitySouth African Medical Research Council Centre for Tuberculosis Research, DST NRF Centre of Excellence for Biomedical Tuberculosis research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch UniversityPathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST)Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute & South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape TownMolecular and Experimental Mycobacteriology, Research Center BorstelDivision of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and PreventionMolecular and Experimental Mycobacteriology, Research Center BorstelCentre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute & South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape TownDivision of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and PreventionPathogen Genomics Laboratory, BESE Division, King Abdullah University of Science and Technology (KAUST)South African Medical Research Council Centre for Tuberculosis Research, DST NRF Centre of Excellence for Biomedical Tuberculosis research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch UniversityAbstract 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.http://link.springer.com/article/10.1186/s12916-019-1487-2TuberculosisDrug-resistantBeyond-XDR-TBMissed resistanceWeakened regimenWhole genome sequencing |
| spellingShingle | 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 A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic BMC Medicine Tuberculosis Drug-resistant Beyond-XDR-TB Missed resistance Weakened regimen Whole genome sequencing |
| title | A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic |
| title_full | A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic |
| title_fullStr | A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic |
| title_full_unstemmed | A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic |
| title_short | A landscape of genomic alterations at the root of a near-untreatable tuberculosis epidemic |
| title_sort | landscape of genomic alterations at the root of a near untreatable tuberculosis epidemic |
| topic | Tuberculosis Drug-resistant Beyond-XDR-TB Missed resistance Weakened regimen Whole genome sequencing |
| url | http://link.springer.com/article/10.1186/s12916-019-1487-2 |
| work_keys_str_mv | AT marisaklopper alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT timhermanusheupink alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT granthillcawthorne alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT elizabethmariastreicher alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT anzaandippenaar alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT margarethadevos alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT abdallahmusaabdallah alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT jasonlimberis alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT matthiasmerker alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT scottburns alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT stefanniemann alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT keertandheda alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT jamesposey alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT arnabpain alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT robinmarkwarren alandscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT marisaklopper landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT timhermanusheupink landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT granthillcawthorne landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT elizabethmariastreicher landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT anzaandippenaar landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT margarethadevos landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT abdallahmusaabdallah landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT jasonlimberis landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT matthiasmerker landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT scottburns landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT stefanniemann landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT keertandheda landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT jamesposey landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT arnabpain landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic AT robinmarkwarren landscapeofgenomicalterationsattherootofanearuntreatabletuberculosisepidemic |