No abstract

dEthambutol 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 ( The mismanagement of patients and inadequate administration of antimicrobial therapy are the most important factors contributing to the development of drug-resistant TB (DR-TB). According to the WHO, DR-TB has become a major public health problem in several settings and, depending on the particular country, 5% of TB new cases and 20% of previously treated cases exhibit simultaneous resistance to isoniazid (INH) and rifampin (RIF) and an aggravated form of DR-TB known as multidrugresistant TB (MDR-TB) (2).Ethambutol (EMB) was introduced in 1961 as a bacteriostatic agent effective against actively growing mycobacteria. It is currently used in combination with other first-line drugs, such as INH and RIF, for the treatment of new TB cases and, depending on the resistance profile, retreatment cases (3). Resistance to EMB has been associated with acquired mutations in the emb cluster of three contiguous genes named embC, embA, and embB (4, 5). The embA and embB genes encode arabinosyl transferases involved in the arabinosylation of arabinogalactan, while embC is implicated in the arabinosylation of lipoarabinomannan (6-8).Several studies have identified mutations at codon 306 of embB as the most common alterations in EMB-resistant (EMB r ) isolates (9-20). However, the occurrence of embB codon 306 mutations in EMB-susceptible isolates (EMB s ) and the absence of mutations in EMB r isolates have raised questions regarding the utility of this codon as a potential marker for resistance (11,19,(21)(22)(23)(24). In addition, a significant increase in the proportion of MDR-TB strains bearing embB 306 mutations has recently been observed (25, 26), and 10 mutations from codons 306 to 508 of embB have been suggested as candidate markers for the prediction of quadruple resistance to INH, RIF, streptomycin (STR), and EMB (27). The identification of mu...