title: Mutations in the embB locus among Korean clinical isolates of Mycobacterium tuberculosis resistant to ethambutol.
abstract: Resistance of Mycobacterium tuberculosis to ethambutol (EMB) has been assigned to an operon, embCAB, which has been proposed to be a structural gene for mycobacterial arabinosyl transferases. Recently, genetic events resulting in structural mutations at embB have been proposed as major contributors to the EMB-resistance of isolates whose minimum inhibitory concentration (MIC) level is higher than 20 microgram/ml. On the contrary, isolates with a MIC level lower than 20 microgram/ml do not seem to contain any sequence alterations. In this study, in an effort to understand the role of embB mutations at a low-level of EMB resistance, we investigated the sequence polymorphisms of clinical isolates whose MIC levels are lower than 10 microgram/ml. Accordingly, the sequence alterations of a 312-bp region of the embB gene containing the 306th codon, which has been assigned as a hot-spot for EMB-resistance related mutations, were determined for 21 EMB-resistant and 5 EMB-susceptible clinical isolates. In brief, among 21 EMB- resistant isolates examined, 12 (57.1%) contained mutations in embB (10 at the 306th codon and 2 at other sites), and the remaining isolates 9 contained no mutations in any region of embB. The observed mutations included M306V, M306I, and M306L substitutions that have been reported previously. However, 3 were novel types, which included M306T, A313G and Y319C, D328Y [corrected] double substitutions. On the other hand, all of the EMB-susceptible isolates were found to be free of mutations. In conclusion, our findings suggest that sequence polymorphism of embB may play a pivotal role in the EMB- resistance of M. tuberculosis.
authors.affiliation: Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, C.P.O. Box 8044, Seoul 120-752, Korea.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Han Jung
authors.initials: HJ
authors.lastname: Myoung
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Bang
authors.forename: Gill-Han
authors.initials: GH
authors.lastname: Bai
authors.forename: Sang-Jae
authors.initials: SJ
authors.lastname: Kim
authors.forename: Joo Deuk
authors.initials: JD
authors.lastname: Kim
authors.forename: Sang-Nae
authors.initials: SN
authors.lastname: Cho
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D002874:Chromosome Mapping; D024881:Drug Resistance, Bacterial; D004977:Ethambutol / Q000494:pharmacology*; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D010430:Pentosyltransferases / Q000235:genetics*; D016133:Polymerase Chain Reaction
chemical_list: D000995:Antitubercular Agents; D004977:Ethambutol; D010430:Pentosyltransferases; C101967:arabinosyltransferase