Mutation at embB codon 306, a potential marker for the identification of multidrug resistance associated with ethambutol in Mycobacterium tuberculosis

• Published in: Antimicrobial agents and chemotherapy 2015-09, Vol.59 (9), p.5455-5462
• Main Authors: Cuevas-Córdoba, Betzaida, Juárez-Eusebio, Dulce María, Almaraz-Velasco, Raquel, Muñiz-Salazar, Raquel, Laniado-Laborin, Rafael, Zenteno-Cuevas, Roberto
• Format: Article
• Language: English
• Subjects: Antitubercular Agents; Antitubercular Agents - pharmacology; Ethambutol; Ethambutol - pharmacology; Mechanisms of Resistance; Microbial Sensitivity Tests; Mutation - genetics; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - metabolism; Pentosyltransferases; Pentosyltransferases - genetics; Pentosyltransferases - metabolism; Tuberculosis, Multidrug-Resistant - genetics
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00117-15

Ethambutol inhibits arabinogalactan and lipoarabinomannan biosynthesis in mycobacteria. The occurrence of mutations in embB codon 306 in ethambutol-susceptible isolates and their absence in resistant isolates has raised questions regarding the utility of this codon as a potential marker for resistance against ethambutol. The characterization of mutations on embB 306 will contribute to a better understanding of the mechanisms of resistance to this drug; therefore, the purpose of this study was to investigate the association between embB 306 mutations and first-line drug resistance profiles in tuberculosis isolates. We sequenced the region surrounding the embB 306 codon in 175 tuberculosis clinical isolates, divided according to drug sensitivity, in three groups: 110 were resistant to at least one first-line drug, of which 61 were resistant to ethambutol (EMB(r)), 49 were sensitive to ethambutol (EMB(s)) but were resistant to another drug, and 65 were pansensitive isolates (P(s)). The associations between embB 306 mutations and phenotypic resistance to all first-line drugs were determined, and their validity and safety as a diagnostic marker were assessed. One of the P(s) isolates (1/65), one of the EMB(s) isolates (1/49), and 20 of the EMB(r) isolates (20/61) presented with an embB 306 mutation. Four different single-nucleotide polymorphisms (SNPs) at embB 306 were associated with simultaneous resistance to ethambutol, isoniazid, and rifampin (odds ratio [OR], 17.7; confidence interval [CI], 5.6 to 56.1) and showed a positive predictive value of 82%, with a specificity of 97% for diagnosing multidrug resistance associated with ethambutol, indicating its potential as a molecular marker for several drugs.