Whole-genome sequencing as a tool for studying the microevolution of drug-resistant serial Mycobacterium tuberculosis isolates

Jaciara de Lourdes do Carmo Guimarães Diniz; Andrea von Groll; Gisela Unis; Elis Regina Dalla-Costa; Maria Lúcia Rosa Rossetti; Júlia Silveira Vianna; Daniela Fernandes Ramos; Ana Júlia Reis; Priscila Cristina Bartolomeu Halicki; João Luis Rheingantz Scaini; Yasmin Castillos de Ibrahim das Neves; Jody Phelan; Ana Rita Gomes; Susana Campino; Karina dos Santos Machado; Adriano Velasque Werhli; Arnab Pain; Taane G. Clark; João Perdigão; Miguel Viveiros; Isabel Portugal; Pedro Eduardo Almeida Silva

doi:10.1016/j.tube.2021.102137

Whole-genome sequencing as a tool for studying the microevolution of drug-resistant serial Mycobacterium tuberculosis isolates

Jaciara de Lourdes do Carmo Guimarães Diniz, Andrea von Groll, Gisela Unis, Elis Regina Dalla-Costa, Maria Lúcia Rosa Rossetti, Júlia Silveira Vianna, Daniela Fernandes Ramos, Ana Júlia Reis, Priscila Cristina Bartolomeu Halicki, João Luis Rheingantz Scaini, Yasmin Castillos de Ibrahim das Neves, Jody Phelan, Ana Rita Gomes, Susana Campino, Karina dos Santos Machado, Adriano Velasque Werhli, Arnab Pain, Taane G. Clark, João Perdigão, Miguel ViveirosIsabel Portugal, Pedro Eduardo Almeida Silva

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Abstract

Treatment of drug-resistant tuberculosis requires extended use of more toxic and less effective drugs and may result in retreatment cases due to failure, abandonment or disease recurrence. It is therefore important to understand the evolutionary process of drug resistance in Mycobacterium tuberculosis. We here in describe the microevolution of drug resistance in serial isolates from six previously treated patients. Drug resistance was initially investigated through phenotypic methods, followed by genotypic approaches. The use of whole-genome sequencing allowed the identification of mutations in the katG, rpsL and rpoB genes associated with drug resistance, including the detection of rare mutations in katG and mixed populations of strains. Molecular docking simulation studies of the impact of observed mutations on isoniazid binding were also performed. Whole-genome sequencing detected 266 single nucleotide polymorphisms between two isolates obtained from one patient, suggesting a case of exogenous reinfection. In conclusion, sequencing technologies can detect rare mutations related to drug resistance, identify subpopulations of resistant strains, and identify diverse populations of strains due to exogenous reinfection, thus improving tuberculosis control by guiding early implementation of appropriate clinical and therapeutic interventions.

Original language	English (US)
Pages (from-to)	102137
Journal	Tuberculosis
Volume	131
DOIs	https://doi.org/10.1016/j.tube.2021.102137
State	Published - Oct 5 2021

Bibliographical note

KAUST Repository Item: Exported on 2021-10-26
Acknowledged KAUST grant number(s): BAS/1/1020-01-01
Acknowledgements: JLCGD was a Fellow of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), PEAS is a Fellow of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) productivity. The study had financial support by Project CNPq/Universal (401963/2016–0), CAPES (PVE-CAPES, 88881.064961/2014–01) and Fundação para a Ciência e Tecnologia (FCT), Portugal [UID/DTP/04138/2019]. This work was carried out with the support of the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) to working mission within the scope of the Capes-Print Program, Financing Code 001". JP was supported by FCT through Estímulo Individual ao Emprego Científico [CEECIND/00394/2017]. JEP is funded by a Newton Institutional Links Grant (British Council, no. 261868591). TGC is funded by the Medical Research Council UK (Grant no. MR/M01360X/1, MR/N010469/1, MR/R025576/1, and MR/R020973/1) and BBSRC (Grant no. BB/R013063/1). SC is funded by Medical Research Council UK grants (ref. MR/M01360X/1, MR/R025576/1, and MR/R020973/1). AP is funded by a faculty baseline fund (BAS/1/1020-01-01) from KAUST.Special thanks to Dear Ruth McNerney for her support and help. We would also like to thank the Universidade Federal do Rio Grande, Faculdade de Farmácia of the Universidade de Lisboa, Instituto de Higiene e Medicina Tropical of the Universidade Nova de Lisboa, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for the structural support needed to realization this study.

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10.1016/j.tube.2021.102137

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de Lourdes do Carmo Guimarães Diniz, J., von Groll, A., Unis, G., Dalla-Costa, E. R., Rosa Rossetti, M. L., Vianna, J. S., Ramos, D. F., Reis, A. J., Bartolomeu Halicki, P. C., Rheingantz Scaini, J. L., Castillos de Ibrahim das Neves, Y., Phelan, J., Gomes, A. R., Campino, S., Machado, K. D. S., Werhli, A. V., Pain, A., Clark, T. G., Perdigão, J., ... Almeida Silva, P. E. (2021). Whole-genome sequencing as a tool for studying the microevolution of drug-resistant serial Mycobacterium tuberculosis isolates. Tuberculosis, 131, 102137. https://doi.org/10.1016/j.tube.2021.102137

@article{99f814d2175148618d35347cff3b3b22,

title = "Whole-genome sequencing as a tool for studying the microevolution of drug-resistant serial Mycobacterium tuberculosis isolates",

abstract = "Treatment of drug-resistant tuberculosis requires extended use of more toxic and less effective drugs and may result in retreatment cases due to failure, abandonment or disease recurrence. It is therefore important to understand the evolutionary process of drug resistance in Mycobacterium tuberculosis. We here in describe the microevolution of drug resistance in serial isolates from six previously treated patients. Drug resistance was initially investigated through phenotypic methods, followed by genotypic approaches. The use of whole-genome sequencing allowed the identification of mutations in the katG, rpsL and rpoB genes associated with drug resistance, including the detection of rare mutations in katG and mixed populations of strains. Molecular docking simulation studies of the impact of observed mutations on isoniazid binding were also performed. Whole-genome sequencing detected 266 single nucleotide polymorphisms between two isolates obtained from one patient, suggesting a case of exogenous reinfection. In conclusion, sequencing technologies can detect rare mutations related to drug resistance, identify subpopulations of resistant strains, and identify diverse populations of strains due to exogenous reinfection, thus improving tuberculosis control by guiding early implementation of appropriate clinical and therapeutic interventions.",

author = "{de Lourdes do Carmo Guimar{\~a}es Diniz}, Jaciara and {von Groll}, Andrea and Gisela Unis and Dalla-Costa, {Elis Regina} and {Rosa Rossetti}, {Maria L{\'u}cia} and Vianna, {J{\'u}lia Silveira} and Ramos, {Daniela Fernandes} and Reis, {Ana J{\'u}lia} and {Bartolomeu Halicki}, {Priscila Cristina} and {Rheingantz Scaini}, {Jo{\~a}o Luis} and {Castillos de Ibrahim das Neves}, Yasmin and Jody Phelan and Gomes, {Ana Rita} and Susana Campino and Machado, {Karina dos Santos} and Werhli, {Adriano Velasque} and Arnab Pain and Clark, {Taane G.} and Jo{\~a}o Perdig{\~a}o and Miguel Viveiros and Isabel Portugal and {Almeida Silva}, {Pedro Eduardo}",

note = "KAUST Repository Item: Exported on 2021-10-26 Acknowledged KAUST grant number(s): BAS/1/1020-01-01 Acknowledgements: JLCGD was a Fellow of Coordena{\c c}{\~a}o de Aperfei{\c c}oamento de Pessoal de N{\'i}vel Superior (CAPES), PEAS is a Fellow of Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico (CNPq) productivity. The study had financial support by Project CNPq/Universal (401963/2016–0), CAPES (PVE-CAPES, 88881.064961/2014–01) and Funda{\c c}{\~a}o para a Ci{\^e}ncia e Tecnologia (FCT), Portugal [UID/DTP/04138/2019]. This work was carried out with the support of the Coordena{\c c}{\~a}o de Aperfei{\c c}oamento de Pessoal de N{\'i}vel Superior - Brazil (CAPES) to working mission within the scope of the Capes-Print Program, Financing Code 001{"}. JP was supported by FCT through Est{\'i}mulo Individual ao Emprego Cient{\'i}fico [CEECIND/00394/2017]. JEP is funded by a Newton Institutional Links Grant (British Council, no. 261868591). TGC is funded by the Medical Research Council UK (Grant no. MR/M01360X/1, MR/N010469/1, MR/R025576/1, and MR/R020973/1) and BBSRC (Grant no. BB/R013063/1). SC is funded by Medical Research Council UK grants (ref. MR/M01360X/1, MR/R025576/1, and MR/R020973/1). AP is funded by a faculty baseline fund (BAS/1/1020-01-01) from KAUST.Special thanks to Dear Ruth McNerney for her support and help. We would also like to thank the Universidade Federal do Rio Grande, Faculdade de Farm{\'a}cia of the Universidade de Lisboa, Instituto de Higiene e Medicina Tropical of the Universidade Nova de Lisboa, Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico (CNPq) and Coordena{\c c}{\~a}o de Aperfei{\c c}oamento de Pessoal de N{\'i}vel Superior (CAPES) for the structural support needed to realization this study.",

year = "2021",

month = oct,

day = "5",

doi = "10.1016/j.tube.2021.102137",

language = "English (US)",

volume = "131",

pages = "102137",

journal = "Tuberculosis",

issn = "1873-281X",

publisher = "Churchill Livingstone",

}

de Lourdes do Carmo Guimarães Diniz, J, von Groll, A, Unis, G, Dalla-Costa, ER, Rosa Rossetti, ML, Vianna, JS, Ramos, DF, Reis, AJ, Bartolomeu Halicki, PC, Rheingantz Scaini, JL, Castillos de Ibrahim das Neves, Y, Phelan, J, Gomes, AR, Campino, S, Machado, KDS, Werhli, AV, Pain, A, Clark, TG, Perdigão, J, Viveiros, M, Portugal, I & Almeida Silva, PE 2021, 'Whole-genome sequencing as a tool for studying the microevolution of drug-resistant serial Mycobacterium tuberculosis isolates', Tuberculosis, vol. 131, pp. 102137. https://doi.org/10.1016/j.tube.2021.102137

TY - JOUR

T1 - Whole-genome sequencing as a tool for studying the microevolution of drug-resistant serial Mycobacterium tuberculosis isolates

AU - de Lourdes do Carmo Guimarães Diniz, Jaciara

AU - von Groll, Andrea

AU - Unis, Gisela

AU - Dalla-Costa, Elis Regina

AU - Rosa Rossetti, Maria Lúcia

AU - Vianna, Júlia Silveira

AU - Ramos, Daniela Fernandes

AU - Reis, Ana Júlia

AU - Bartolomeu Halicki, Priscila Cristina

AU - Rheingantz Scaini, João Luis

AU - Castillos de Ibrahim das Neves, Yasmin

AU - Phelan, Jody

AU - Gomes, Ana Rita

AU - Campino, Susana

AU - Machado, Karina dos Santos

AU - Werhli, Adriano Velasque

AU - Pain, Arnab

AU - Clark, Taane G.

AU - Perdigão, João

AU - Viveiros, Miguel

AU - Portugal, Isabel

AU - Almeida Silva, Pedro Eduardo

N1 - KAUST Repository Item: Exported on 2021-10-26 Acknowledged KAUST grant number(s): BAS/1/1020-01-01 Acknowledgements: JLCGD was a Fellow of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), PEAS is a Fellow of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) productivity. The study had financial support by Project CNPq/Universal (401963/2016–0), CAPES (PVE-CAPES, 88881.064961/2014–01) and Fundação para a Ciência e Tecnologia (FCT), Portugal [UID/DTP/04138/2019]. This work was carried out with the support of the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) to working mission within the scope of the Capes-Print Program, Financing Code 001". JP was supported by FCT through Estímulo Individual ao Emprego Científico [CEECIND/00394/2017]. JEP is funded by a Newton Institutional Links Grant (British Council, no. 261868591). TGC is funded by the Medical Research Council UK (Grant no. MR/M01360X/1, MR/N010469/1, MR/R025576/1, and MR/R020973/1) and BBSRC (Grant no. BB/R013063/1). SC is funded by Medical Research Council UK grants (ref. MR/M01360X/1, MR/R025576/1, and MR/R020973/1). AP is funded by a faculty baseline fund (BAS/1/1020-01-01) from KAUST.Special thanks to Dear Ruth McNerney for her support and help. We would also like to thank the Universidade Federal do Rio Grande, Faculdade de Farmácia of the Universidade de Lisboa, Instituto de Higiene e Medicina Tropical of the Universidade Nova de Lisboa, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for the structural support needed to realization this study.

PY - 2021/10/5

Y1 - 2021/10/5

N2 - Treatment of drug-resistant tuberculosis requires extended use of more toxic and less effective drugs and may result in retreatment cases due to failure, abandonment or disease recurrence. It is therefore important to understand the evolutionary process of drug resistance in Mycobacterium tuberculosis. We here in describe the microevolution of drug resistance in serial isolates from six previously treated patients. Drug resistance was initially investigated through phenotypic methods, followed by genotypic approaches. The use of whole-genome sequencing allowed the identification of mutations in the katG, rpsL and rpoB genes associated with drug resistance, including the detection of rare mutations in katG and mixed populations of strains. Molecular docking simulation studies of the impact of observed mutations on isoniazid binding were also performed. Whole-genome sequencing detected 266 single nucleotide polymorphisms between two isolates obtained from one patient, suggesting a case of exogenous reinfection. In conclusion, sequencing technologies can detect rare mutations related to drug resistance, identify subpopulations of resistant strains, and identify diverse populations of strains due to exogenous reinfection, thus improving tuberculosis control by guiding early implementation of appropriate clinical and therapeutic interventions.

AB - Treatment of drug-resistant tuberculosis requires extended use of more toxic and less effective drugs and may result in retreatment cases due to failure, abandonment or disease recurrence. It is therefore important to understand the evolutionary process of drug resistance in Mycobacterium tuberculosis. We here in describe the microevolution of drug resistance in serial isolates from six previously treated patients. Drug resistance was initially investigated through phenotypic methods, followed by genotypic approaches. The use of whole-genome sequencing allowed the identification of mutations in the katG, rpsL and rpoB genes associated with drug resistance, including the detection of rare mutations in katG and mixed populations of strains. Molecular docking simulation studies of the impact of observed mutations on isoniazid binding were also performed. Whole-genome sequencing detected 266 single nucleotide polymorphisms between two isolates obtained from one patient, suggesting a case of exogenous reinfection. In conclusion, sequencing technologies can detect rare mutations related to drug resistance, identify subpopulations of resistant strains, and identify diverse populations of strains due to exogenous reinfection, thus improving tuberculosis control by guiding early implementation of appropriate clinical and therapeutic interventions.

UR - http://hdl.handle.net/10754/672941

UR - https://linkinghub.elsevier.com/retrieve/pii/S1472979221000871

UR - http://www.scopus.com/inward/record.url?scp=85117228734&partnerID=8YFLogxK

U2 - 10.1016/j.tube.2021.102137

DO - 10.1016/j.tube.2021.102137

M3 - Article

C2 - 34673379

SN - 1873-281X

VL - 131

SP - 102137

JO - Tuberculosis

JF - Tuberculosis

ER -

Whole-genome sequencing as a tool for studying the microevolution of drug-resistant serial Mycobacterium tuberculosis isolates

Abstract

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