Correlating genetic mutations with isoniazid phenotypic levels of resistance in Mycobacterium tuberculosis isolates from patients with drug-resistant tuberculosis in a high burden setting

Autor(es)

Watanabe Pinhata, Juliana Maira ^[1] ; Brandao, Angela Pires ^{[1, 2]} ; Mendes, Flavia de Freitas ^[1] ; da Silva Rabello, Michelle Christiane ^[3] ; Ferrazoli, Lucilaine ^[1] ; de Oliveira, Rosangela Siqueira ^[1]

Afiliação do(s) autor(es)

^[1] Inst Adolfo Lutz IAL, Ctr Bacteriol, Nucleo TB & Micobacterioses, Av Dr Arnaldo 351, 9 Andar, BR-01246000 Sao Paulo, SP - Brazil

^[2] Fiocruz MS, Fundacao Oswaldo Cruz, Inst Oswaldo Cruz, Av Brasil 4365, BR-21040360 Rio De Janeiro, RJ - Brazil

^[3] Fiocruz MS, Fundacao Oswaldo Cruz, Ctr Pesquisas Aggeu Magalhaes, Av Prof Moraes Rego S-N, Cidade Univ, BR-50740465 Recife, PE - Brazil

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES; v. 40, n. 12 JUL 2021.
• Citações Web of Science: 0

Resumo

We analysed mutations in katG, inhA and rpoB genes, and isoniazid phenotypic resistance levels in Mycobacterium tuberculosis isolates from drug-resistant TB patients from SAo Paulo state, Brazil. Isolates resistant to the critical concentration of isoniazid in MGIT (0.1 mu g/mL) were screened for mutations in katG 315 codon, inhA promoter region and rpoB RRDR by MTBDRplus assay and subjected to determination of isoniazid resistance levels by MGIT 960. Discordances were resolved by Sanger sequencing. Among the 203 isolates studied, 109 (54%) were isoniazid-monoresistant, 47 (23%) MDR, 29 (14%) polydrug-resistant, 12 (6%) pre-XDR and 6 (3%) XDR. MTBDRplus detected isoniazid mutations in 75% (153/203) of the isolates. Sequencing of the entire katG and inhA genes revealed mutations in 18/50 wild-type isolates by MTBDRplus (10 with novel mutations), resulting in a total of 32/203 (16%) isolates with no mutations detected. 81/83 (98%) isolates with katG 315 mutations alone had intermediate resistance. Of the 66 isolates with inhA C-15T mutation alone, 51 (77%) showed low-level, 14 (21%) intermediate and 1 (2%) high-level resistance. 5/6 (83%) isolates with mutations in both katG and inhA had high-level resistance. Inferred mutations corresponded to 22% (16/73) of all mutations found in rpoB. Mutations detected in katG regions other than codon 315 in this study might be potential new isoniazid resistance markers and could explain phenotypic resistance in some isolates without katG and inhA classic mutations. In our setting, 16% of isoniazid-resistant isolates, some with high-level resistance, presented no mutations either in katG or inhA. (AU)

• Processo FAPESP: 12/51756-5 - Avaliação de desenvolvimento de métodos rápidos para o diagnóstico da tuberculose multirresistente e extensivamente resistente e aplicabilidade em um laboratório de referência
• Beneficiário: Lucilaine Ferrazoli
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisa em Políticas Públicas para o SUS
• Processo FAPESP: 17/16082-7 - Caracterização de mutações em isolados clínicos de Mycobacterium tuberculosis resistentes aos fármacos de 1ª e 2ª linha e relação entre as mutações e os níveis fenotípicos de resistência à isoniazida.
• Beneficiário: Rosangela Siqueira de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Regular