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Antimicrobial Agents and Chemotherapy, June 2008, p. 2027-2034, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01486-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Transfer of embB Codon 306 Mutations into Clinical Mycobacterium tuberculosis Strains Alters Susceptibility to Ethambutol, Isoniazid, and Rifampin{triangledown} ,{dagger}

Hassan Safi, Brendan Sayers, Manzour H. Hazbón, and David Alland*

Division of Infectious Disease and the Center for Emerging Pathogens, Department of Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103

Received 15 November 2007/ Returned for modification 14 January 2008/ Accepted 24 March 2008

Implicated as a major mechanism of ethambutol (EMB) resistance in clinical studies of Mycobacterium tuberculosis, mutations in codon 306 of the embB gene (embB306) have also been detected in EMB-susceptible clinical isolates. Other studies have found strong associations between embB306 mutations and multidrug resistance, but not EMB resistance. We performed allelic exchange studies in EMB-susceptible and EMB-resistant clinical M. tuberculosis isolates to identify the role of embB306 mutations in any type of drug resistance. Replacing wild-type embB306 ATG from EMB-susceptible clinical M. tuberculosis strain 210 with embB306 ATA, ATC, CTG, or GTG increased the EMB MIC from 2 µg/ml to 7, 7, 8.5, and 14 µg/ml, respectively. Replacing embB306 ATC or GTG from two high-level EMB-resistant clinical strains with wild-type ATG lowered EMB MICs from 20 µg/ml or 28 µg/ml, respectively, to 3 µg/ml. All parental and isogenic mutant strains had identical isoniazid (INH) and rifampin (RIF) MICs. However, embB306 CTG mutants had growth advantages compared to strain 210 at sub-MICs of INH or RIF in monocultures and at sub-MICs of INH in competition assays. CTG mutants were also more resistant to the additive or synergistic activities of INH, RIF, or EMB used in different combinations. These results demonstrate that embB306 mutations cause an increase in the EMB MIC, a variable degree of EMB resistance, and are necessary but not sufficient for high-level EMB resistance. The unusual growth property of embB306 mutants in other antibiotics suggests that they may be amplified during treatment in humans and that a single mutation may affect antibiotic susceptibility against multiple first-line antibiotics.

* Corresponding author. Mailing address: Division of Infectious Disease, University of Medicine and Dentistry of New Jersey, Department of Medicine, MSB920C, 185 South Orange Ave., Newark, NJ 07103. Phone: (973) 972-2179. Fax: (973) 972-0713. E-mail: allandda{at}umdnj.edu

{triangledown} Published ahead of print on 31 March 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, June 2008, p. 2027-2034, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01486-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hillemann, D., Rusch-Gerdes, S., Richter, E. (2009). Feasibility of the GenoType MTBDRsl Assay for Fluoroquinolone, Amikacin-Capreomycin, and Ethambutol Resistance Testing of Mycobacterium tuberculosis Strains and Clinical Specimens. J. Clin. Microbiol. 47: 1767-1772 [Abstract] [Full Text]  
  • Starks, A. M., Gumusboga, A., Plikaytis, B. B., Shinnick, T. M., Posey, J. E. (2009). Mutations at embB Codon 306 Are an Important Molecular Indicator of Ethambutol Resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 53: 1061-1066 [Abstract] [Full Text]  
  • Hazbon, M. H., Motiwala, A. S., Cavatore, M., Brimacombe, M., Whittam, T. S., Alland, D. (2008). Convergent Evolutionary Analysis Identifies Significant Mutations in Drug Resistance Targets of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 52: 3369-3376 [Abstract] [Full Text]  
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