Ethambutol resistance in Mycobacterium tuberculosis: Critical role of embB mutations

Srinand Sreevatsan, Kathryn E. Stockbauer, Xi Pan, Barry N. Kreiswirth, Soraya L. Moghazeh, William R. Jacobs, Amalio Telenti, James M. Musser

Research output: Contribution to journalArticle

Abstract

Ethambutol [(S,S')-2,2'-(ethylenediimino)di-1-butanol; EMB], is a first- line drug used to treat tuberculosis. To gain insight into the molecular basis of EMB resistance, we characterized the 10-kb embCAB locus in 16 EMB- resistant and 3 EMB-susceptible genetically distinct Mycobacterium tuberculosis strains from diverse localities by automated DNA sequencing and single-stranded conformation polymorphism analysis. All 19 organisms had virtually identical sequences for the entire 10-kb region. Eight EMB- resistant organisms had mutations located in codon 306 of embB that resulted in the replacement of the wild-type Met residue with Ile or Val. Automated sequence analysis of the 5' region (1,892 bp) of embB in an additional 69 EMB-resistant and 30 EMB-susceptible M. tuberculosis isolates from diverse geographic localities and representing 70 distinct IS6110 fingerprints confirmed the unique association of substitutions in amino acid residue 306 of EmbB with EMB resistance. Six other embB nucleotide substitutions resulting in four amino acid replacements were uniquely found in resistant strains. Sixty-nine percent of epidemiologically unassociated EMB-resistant organisms had an amino acid substitution not found in susceptible strains, and most (89%) replacements occurred at amino acid residue 306 of EmbB. For strains with the Met306Leu or Met306Val replacements EMB MICs were generally higher (40 μg/ml) than those for organisms with Met306IIe substitutions (20 μg/ml). The data are consistent with the idea that amino acid substitutions in EmbB alter the drug-protein interaction and thereby cause EMB resistance.

Original languageEnglish (US)
Pages (from-to)1677-1681
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume41
Issue number8
StatePublished - Aug 1 1997

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Pentosyltransferases
DNA Mutational Analysis
Molecular Sequence Data
Antitubercular Agents
Single-Stranded Conformational Polymorphism
Bacterial DNA
Ethambutol
Microbial Sensitivity Tests
Amino Acid Substitution
Microbial Drug Resistance
Mycobacterium tuberculosis
Point Mutation
Mutation
Amino Acids
1-Butanol
Dermatoglyphics
DNA Sequence Analysis
Drug Interactions
Codon
Sequence Analysis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Sreevatsan, S., Stockbauer, K. E., Pan, X., Kreiswirth, B. N., Moghazeh, S. L., Jacobs, W. R., ... Musser, J. M. (1997). Ethambutol resistance in Mycobacterium tuberculosis: Critical role of embB mutations. Antimicrobial Agents and Chemotherapy, 41(8), 1677-1681.

Ethambutol resistance in Mycobacterium tuberculosis : Critical role of embB mutations. / Sreevatsan, Srinand; Stockbauer, Kathryn E.; Pan, Xi; Kreiswirth, Barry N.; Moghazeh, Soraya L.; Jacobs, William R.; Telenti, Amalio; Musser, James M.

In: Antimicrobial Agents and Chemotherapy, Vol. 41, No. 8, 01.08.1997, p. 1677-1681.

Research output: Contribution to journalArticle

Sreevatsan, S, Stockbauer, KE, Pan, X, Kreiswirth, BN, Moghazeh, SL, Jacobs, WR, Telenti, A & Musser, JM 1997, 'Ethambutol resistance in Mycobacterium tuberculosis: Critical role of embB mutations', Antimicrobial Agents and Chemotherapy, vol. 41, no. 8, pp. 1677-1681.
Sreevatsan S, Stockbauer KE, Pan X, Kreiswirth BN, Moghazeh SL, Jacobs WR et al. Ethambutol resistance in Mycobacterium tuberculosis: Critical role of embB mutations. Antimicrobial Agents and Chemotherapy. 1997 Aug 1;41(8):1677-1681.
Sreevatsan, Srinand ; Stockbauer, Kathryn E. ; Pan, Xi ; Kreiswirth, Barry N. ; Moghazeh, Soraya L. ; Jacobs, William R. ; Telenti, Amalio ; Musser, James M. / Ethambutol resistance in Mycobacterium tuberculosis : Critical role of embB mutations. In: Antimicrobial Agents and Chemotherapy. 1997 ; Vol. 41, No. 8. pp. 1677-1681.
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