Five-year microevolution of a multidrug-resistant Mycobacterium tuberculosis strain within a patient with inadequate compliance to treatment

BMC Infectious Diseases

Adrián Turjanski¹  Marcelo Martí¹  Beatriz López²  Ingrid Wainmayer²  Roxana Paul²  Josefina Campos²  Norberto Simboli²  Tomás Poklepovich²  Johana Monteserin³  Noemí Yokobori³  Viviana Ritacco³  Federico Serral⁴  Florencia Castello⁴  Darío A. Fernandez Do Porto⁵  Agustín Pardo⁶  Ezequiel J. Sosa⁷  Andrés Fernández Benevento⁷  Mario Matteo⁸ 

[1] Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina;Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, IQUIBICEN, CONICET, Buenos Aires, Argentina;Instituto Nacional de Enfermedades Infecciosas-ANLIS Carlos Malbrán, Buenos Aires, Argentina;Instituto Nacional de Enfermedades Infecciosas-ANLIS Carlos Malbrán, Buenos Aires, Argentina;Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina;Instituto de Cálculo, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina;Instituto de Cálculo, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina;Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina;Instituto de Cálculo, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina;Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, IQUIBICEN, CONICET, Buenos Aires, Argentina;Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales, IQUIBICEN, CONICET, Buenos Aires, Argentina;Instituto de Tisioneumonología Raúl F. Vaccarezza, Hospital de Infecciosas Dr. F. J. Muñiz, Buenos Aires, Argentina;

关键词: Drug resistant tuberculosis;    Multidrug-resistance;    Clonal evolution;    High-throughput nucleotide sequencing;   

DOI  :  10.1186/s12879-021-06069-9

来源: Springer

【 摘 要 】

BackgroundWhole-genome sequencing has shown that the Mycobacterium tuberculosis infection process can be more heterogeneous than previously thought. Compartmentalized infections, exogenous reinfections, and microevolution are manifestations of this clonal complexity. The analysis of the mechanisms causing the microevolution —the genetic variability of M. tuberculosis at short time scales— of a parental strain into clonal variants with a patient is a relevant issue that has not been yet completely addressed. To our knowledge, a whole genome sequence microevolution analysis in a single patient with inadequate adherence to treatment has not been previously reported.Case presentationIn this work, we applied whole genome sequencing analysis for a more in-depth analysis of the microevolution of a parental Mycobacterium tuberculosis strain into clonal variants within a patient with poor treatment compliance in Argentina. We analyzed the whole-genome sequence of 8 consecutive Mycobacterium tuberculosis isolates obtained from a patient within 57-months of intermittent therapy. Nineteen mutations (9 short-term, 10 fixed variants) emerged, most of them associated with drug resistance. The first isolate was already resistant to isoniazid, rifampicin, and streptomycin, thereafter the strain developed resistance to fluoroquinolones and pyrazinamide. Surprisingly, isolates remained susceptible to the pro-drug ethionamide after acquiring a frameshift mutation in ethA, a gene required for its activation. We also found a novel variant, (T-54G), in the 5′ untranslated region of whiB7 (T-54G), a region allegedly related to kanamycin resistance. Notably, discrepancies between canonical and phage-based susceptibility testing to kanamycin were previously found for the isolate harboring this mutation. In our patient, microevolution was mainly driven by drug selective pressure. Rare short-term mutations fixed together with resistance-conferring mutations during therapy.ConclusionsThis report highlights the relevance of whole-genome sequencing analysis in the clinic for characterization of pre-XDR and MDR resistance profile, particularly in patients with incomplete and/or intermittent treatment.

【 授权许可】

CC BY