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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Pages (from-to)102137
JournalTuberculosis
Volume131
DOIs
StatePublished - 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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