Mutations in the embB locus among Korean clinical isolates of Mycobacterium tuberculosis resistant to ethambutol.
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.
Lee
Hye Young
HY
Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, C.P.O. Box 8044, Seoul 120-752, Korea.
Myoung
Han Jung
HJ
Bang
Hye Eun
HE
Bai
Gill-Han
GH
Kim
Sang-Jae
SJ
Kim
Joo Deuk
JD
Cho
Sang-Nae
SN
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
D000995:Antitubercular Agents; D004977:Ethambutol; D010430:Pentosyltransferases; C101967:arabinosyltransferase