Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment
Rubeshan Perumal,1,2 Azraa Khan,1 Kogieleum Naidoo,1,2 Senamile L Ngema,1 Louansha Nandlal,1,2 Nesri Padayatchi,1,2 Navisha Dookie1,2 1Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu Natal, South Africa; 2South African Medical Researc...
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2023-05-01
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| Series: | Infection and Drug Resistance |
| Subjects: | |
| Online Access: | https://www.dovepress.com/mycobacterium-tuberculosis-intra-host-evolution-among-drug-resistant-t-peer-reviewed-fulltext-article-IDR |
| _version_ | 1827950913689485312 |
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| author | Perumal R Khan A Naidoo K Ngema SL Nandlal L Padayatchi N Dookie N |
| author_facet | Perumal R Khan A Naidoo K Ngema SL Nandlal L Padayatchi N Dookie N |
| author_sort | Perumal R |
| collection | DOAJ |
| description | Rubeshan Perumal,1,2 Azraa Khan,1 Kogieleum Naidoo,1,2 Senamile L Ngema,1 Louansha Nandlal,1,2 Nesri Padayatchi,1,2 Navisha Dookie1,2 1Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu Natal, South Africa; 2South African Medical Research Council (SAMRC) – CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Durban, KwaZulu Natal, South AfricaCorrespondence: Rubeshan Perumal, Doris Duke Medical Research Institute (2nd Floor), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Private Bag X7, Congella, Durban, 4013, South Africa, Tel +27 31 260 4555, Fax +27 31 260 4566, Email Rubeshan.perumal@caprisa.orgBackground: Understanding Mycobacterium tuberculosis (Mtb) intra-host evolution of drug resistance is important for successful drug-resistant tuberculosis (DR-TB) treatment and control strategies. This study aimed to characterise the acquisition of genetic mutations and low-frequency variants associated with treatment-emergent Mtb drug resistance in longitudinally profiled clinical isolates from patients who experienced DR-TB treatment failure.Patients and Methods: We performed deep Whole Genome Sequencing on 23 clinical isolates obtained longitudinally across nine timepoints from five patients who experienced DR-TB treatment failure enrolled in the CAPRISA 020 InDEX study. The minimum inhibitory concentrations (MICs) were established on the BACTEC™ MGIT 960™ instrument on 15/23 longitudinal clinical isolates for eight anti-TB drugs (rifampicin, isoniazid, ethambutol, levofloxacin, moxifloxacin, linezolid, clofazimine, bedaquiline).Results: In total, 22 resistance associated mutations/variants were detected. We observed four treatment-emergent mutations in two out of the five patients. Emerging resistance to the fluoroquinolones was associated with 16- and 64-fold elevated levofloxacin (2– 8 mg/L) and moxifloxacin (1– 2 mg/L) MICs, respectively, resulting from the D94G/N and A90V variants in the gyrA gene. We identified two novel mutations associated with elevated bedaquiline MICs (> 66-fold): an emerging frameshift variant (D165) on the Rv0678 gene and R409Q variant on the Rv1979c gene present from baseline.Conclusion: Genotypic and phenotypic resistance to the fluoroquinolones and bedaquiline was acquired in two out of five patients who experienced DR-TB treatment failure. Deep sequencing of multiple longitudinal clinical isolates for resistance-associated mutations coupled with phenotypic MIC testing confirmed intra-host Mtb evolution.Keywords: tuberculosis, phenotypic resistance, drug resistance acquisition, whole genome sequencing, emerging mutations, bedaquiline |
| first_indexed | 2024-04-09T13:33:29Z |
| format | Article |
| id | doaj.art-f5dd5c06b4014d42b08f64f7573e29ae |
| institution | Directory Open Access Journal |
| issn | 1178-6973 |
| language | English |
| last_indexed | 2024-04-09T13:33:29Z |
| publishDate | 2023-05-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Infection and Drug Resistance |
| spelling | doaj.art-f5dd5c06b4014d42b08f64f7573e29ae2023-05-09T18:57:55ZengDove Medical PressInfection and Drug Resistance1178-69732023-05-01Volume 162849285983614Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing TreatmentPerumal RKhan ANaidoo KNgema SLNandlal LPadayatchi NDookie NRubeshan Perumal,1,2 Azraa Khan,1 Kogieleum Naidoo,1,2 Senamile L Ngema,1 Louansha Nandlal,1,2 Nesri Padayatchi,1,2 Navisha Dookie1,2 1Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, KwaZulu Natal, South Africa; 2South African Medical Research Council (SAMRC) – CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Durban, KwaZulu Natal, South AfricaCorrespondence: Rubeshan Perumal, Doris Duke Medical Research Institute (2nd Floor), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Private Bag X7, Congella, Durban, 4013, South Africa, Tel +27 31 260 4555, Fax +27 31 260 4566, Email Rubeshan.perumal@caprisa.orgBackground: Understanding Mycobacterium tuberculosis (Mtb) intra-host evolution of drug resistance is important for successful drug-resistant tuberculosis (DR-TB) treatment and control strategies. This study aimed to characterise the acquisition of genetic mutations and low-frequency variants associated with treatment-emergent Mtb drug resistance in longitudinally profiled clinical isolates from patients who experienced DR-TB treatment failure.Patients and Methods: We performed deep Whole Genome Sequencing on 23 clinical isolates obtained longitudinally across nine timepoints from five patients who experienced DR-TB treatment failure enrolled in the CAPRISA 020 InDEX study. The minimum inhibitory concentrations (MICs) were established on the BACTEC™ MGIT 960™ instrument on 15/23 longitudinal clinical isolates for eight anti-TB drugs (rifampicin, isoniazid, ethambutol, levofloxacin, moxifloxacin, linezolid, clofazimine, bedaquiline).Results: In total, 22 resistance associated mutations/variants were detected. We observed four treatment-emergent mutations in two out of the five patients. Emerging resistance to the fluoroquinolones was associated with 16- and 64-fold elevated levofloxacin (2– 8 mg/L) and moxifloxacin (1– 2 mg/L) MICs, respectively, resulting from the D94G/N and A90V variants in the gyrA gene. We identified two novel mutations associated with elevated bedaquiline MICs (> 66-fold): an emerging frameshift variant (D165) on the Rv0678 gene and R409Q variant on the Rv1979c gene present from baseline.Conclusion: Genotypic and phenotypic resistance to the fluoroquinolones and bedaquiline was acquired in two out of five patients who experienced DR-TB treatment failure. Deep sequencing of multiple longitudinal clinical isolates for resistance-associated mutations coupled with phenotypic MIC testing confirmed intra-host Mtb evolution.Keywords: tuberculosis, phenotypic resistance, drug resistance acquisition, whole genome sequencing, emerging mutations, bedaquilinehttps://www.dovepress.com/mycobacterium-tuberculosis-intra-host-evolution-among-drug-resistant-t-peer-reviewed-fulltext-article-IDRtuberculosisphenotypic resistancedrug resistance acquisitionwhole genome sequencingemerging mutationsbedaquiline. |
| spellingShingle | Perumal R Khan A Naidoo K Ngema SL Nandlal L Padayatchi N Dookie N Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment Infection and Drug Resistance tuberculosis phenotypic resistance drug resistance acquisition whole genome sequencing emerging mutations bedaquiline. |
| title | Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment |
| title_full | Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment |
| title_fullStr | Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment |
| title_full_unstemmed | Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment |
| title_short | Mycobacterium tuberculosis Intra-Host Evolution Among Drug-Resistant Tuberculosis Patients Failing Treatment |
| title_sort | mycobacterium tuberculosis intra host evolution among drug resistant tuberculosis patients failing treatment |
| topic | tuberculosis phenotypic resistance drug resistance acquisition whole genome sequencing emerging mutations bedaquiline. |
| url | https://www.dovepress.com/mycobacterium-tuberculosis-intra-host-evolution-among-drug-resistant-t-peer-reviewed-fulltext-article-IDR |
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