Genome sequencing of Mycobacterium tuberculosis clinical isolates revealed isoniazid resistance mechanisms undetected by conventional molecular methods.
Fiche du document
- doi: 10.1016/j.ijantimicag.2020.106068
- issn: 0924-8579
Ce document est lié à :
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ijantimicag.2020.106068
Ce document est lié à :
info:eu-repo/semantics/altIdentifier/pmid/32603684
Ce document est lié à :
info:eu-repo/semantics/altIdentifier/eissn/1872-7913
Ce document est lié à :
info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_81020030909E0
info:eu-repo/semantics/openAccess , CC BY-NC-ND 4.0 , https://creativecommons.org/licenses/by-nc-nd/4.0/
Citer ce document
S. Laurent et al., « Genome sequencing of Mycobacterium tuberculosis clinical isolates revealed isoniazid resistance mechanisms undetected by conventional molecular methods. », Serveur académique Lausannois, ID : 10.1016/j.ijantimicag.2020.106068
Métriques
Partage / Export
Résumé
A combination of targeted molecular methods and phenotypic drug-susceptibility testing is the most widely used approach to detect drug resistance in Mycobacterium tuberculosis isolates. We report the delay in the introduction of an efficient anti-tuberculous drug regimen because of a M. tuberculosis strain displaying a high level of resistance to isoniazid, in the absence of the common mutations associated with isoniazid-resistance, including katG mutations and inhA promoter mutations. Whole-genome sequencing (WGS) identified a large loss-of-function insertion (>1000 pb) at the end of katG in the isolate together with a -57C>T ahpC mutation, a resistance mechanism that would have remained undetected by a conventional molecular targeted approach. A retrospective search using publicly available WGS data of more than 1200 isoniazid-resistant isolates and a similar sized control dataset of isoniazid-susceptible isolates revealed that most (22/31) isoniazid-resistant, KatG loss-of-function mutants had an associated rare ahpC promoter mutation. In contrast, only 7 of 1411 isoniazid-susceptible strains carried a rare ahpC promoter mutation, including shared mutations with the 31 isoniazid-resistant KatG loss-of-function mutants. These results indicate that rare ahpC promoter mutations could be used as a proxy for investigating simultaneous KatG loss-of-function or missense mutations. In addition, WGS in routine diagnosis would improve drug susceptibility testing in M. tuberculosis clinical isolates and is an efficient tool for detecting resistance mechanisms undetected by conventional molecular methods.