Identification of novel mutations associated with cycloserine resistance in Mycobacterium tuberculosis.
J Antimicrob Chemother
; 72(12): 3272-3276, 2017 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-28961957
ABSTRACT
OBJECTIVES:
d-Cycloserine is an important second-line drug used to treat MDR- and XDR-TB. However, the mechanisms of resistance to d-cycloserine are not well understood. Here we investigated the molecular basis of d-cycloserine resistance using in vitro-isolated resistant mutants.METHODS:
Mycobacterium tuberculosis H37Rv was subjected to mutant selection on 7H11 agar plates containing varying concentrations of d-cycloserine. A total of 18 d-cycloserine-resistant mutants were isolated and subjected to WGS. The identified mutations associated with d-cycloserine resistance were confirmed by PCR and Sanger sequencing.RESULTS:
We identified mutations in 16 genes that are associated with d-cycloserine resistance. Interestingly, we found mutations only in alr (rv3423c) encoding alanine racemase, but not in other known d-cycloserine resistance-associated genes such as ddl, cycA or ald. Instead, we identified 13 new genes [rv0059, betP (rv0917), rv0221, rv1403c, rv1683, rv1726, gabD2 (rv1731), rv2749, sugI (rv3331), hisC2 (rv3772), the 5' intergenic region of rv3345c and rv1435c, and the 3' region of rv0759c] that had solo mutations associated with d-cycloserine resistance. Our findings indicate that the mechanisms of d-cycloserine resistance are more complex than previously thought and involve genes participating in different cellular functions such as lipid metabolism, methyltransferase, the stress response and transport systems.CONCLUSIONS:
New mutations in diverse genes associated with d-cycloserine resistance have been identified that shed new light on the mechanisms of action and resistance of d-cycloserine. Future studies are needed to verify these findings in clinical strains so that molecular detection of d-cycloserine resistance for improved treatment of MDR-TB can be developed.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ciclosserina
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Farmacorresistência Bacteriana
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Antibióticos Antituberculose
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Mutação
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Mycobacterium tuberculosis
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Revista:
J Antimicrob Chemother
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
China