emb nucleotide polymorphisms and the role of embB306 mutations in Mycobacterium tuberculosis resistance to ethambutol

The emb locus has been considered a target for ethambutol (EMB). Substitutions of codon 306 in Mycobacterium tuberculosis embB have been shown to be the most frequent and predictive mutations for EMB resistance; however, recent reports question the biological role of this mutation. We sequenced embB, embC and embR of 44 EMB-resistant M. tuberculosis strains and found that 30/44 (68.1%) strains had a resistance-associated mutation in one of the three genes sequenced. The majority of these mutations resulted in amino acid replacements at codon 306, 368, 378, and 406 of EmbB. The most common mutation reported in EmbC was at codon 270, followed by mutation at codon 297. Novel mutations were also reported in EmbR. Mutations in embC and embR were usually present together with mutations in embB. We found 41/44 EMB-resistant isolates to be resistant to other antituberculosis drugs as well. Our data confirm that mutation at emb306 does not confer resistance to EMB but is a rather common polymorphism in clinical strains of M. tuberculosis predisposing them to the development of any type of drug resistance.