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Antimicrobial Agents and Chemotherapy, September 2005, p. 3794-3802, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3794-3802.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Role of embB Codon 306 Mutations in Mycobacterium tuberculosis Revisited: a Novel Association with Broad Drug Resistance and IS6110 Clustering Rather than Ethambutol Resistance

Manzour Hernando Hazbón,1 Miriam Bobadilla del Valle,2 Marta Inírida Guerrero,3 Mandira Varma-Basil,4 Ingrid Filliol,1 Magali Cavatore,1 Roberto Colangeli,1 Hassan Safi,1 Helen Billman-Jacobe,5 Caroline Lavender,5 Janet Fyfe,6 Lourdes García-García,2 Amy Davidow,7 Michael Brimacombe,7 Clara Inés León,3 Tania Porras,3 Mridula Bose,4 Fernando Chaves,8 Kathleen D. Eisenach,9 José Sifuentes-Osornio,2 Alfredo Ponce de León,2 M. Donald Cave,9 and David Alland1*

Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Reemerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103,1 Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico,2 Grupo de Micobacterias, Subdirección de Investigación, Instituto Nacional de Salud, Bogotá, Colombia,3 Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110007, India,4 Department of Microbiology and Immunology, University of Melbourne, Royal Parade, Parkville, Victoria 3010, Australia,5 Victorian Mycobacterium Reference Laboratory, Victorian Infectious Diseases Reference Laboratory, North Melbourne Victoria 3051, Australia,6 Department of Preventive Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103,7 Servicio de Microbiología, Hospital Universitario Doce de Octubre, 28041 Madrid, Spain,8 Central Arkansas Veterans Healthcare System, Departments of Pathology, Microbiology-Immunology, and Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 722059

Received 12 April 2005/ Returned for modification 13 May 2005/ Accepted 10 June 2005

Mutations at position 306 of embB (embB306) have been proposed as a marker for ethambutol resistance in Mycobacterium tuberculosis; however, recent reports of embB306 mutations in ethambutol-susceptible isolates caused us to question the biological role of this mutation. We tested 1,020 clinical M. tuberculosis isolates with different drug susceptibility patterns and of different geographical origins for associations between embB306 mutations, drug resistance patterns, and major genetic group. One hundred isolates (10%) contained a mutation in embB306; however, only 55 of these mutants were ethambutol resistant. Mutations in embB306 could not be uniquely associated with any particular type of drug resistance and were found in all three major genetic groups. A striking association was observed between these mutations and resistance to any drug (P < 0.001), and the association between embB306 mutations and resistance to increasing numbers of drugs was highly significant (P < 0.001 for trend). We examined the association between embB306 mutations and IS6110 clustering (as a proxy for transmission) among all drug-resistant isolates. Mutations in embB306 were significantly associated with clustering by univariate analysis (odds ratio, 2.44; P = 0.004). In a multivariate model that also included mutations in katG315, katG463, gyrA95, and kasA269, only mutations in embB306 (odds ratio, 2.14; P = 0.008) and katG315 (odds ratio, 1.99; P = 0.015) were found to be independently associated with clustering. In conclusion, embB306 mutations do not cause classical ethambutol resistance but may predispose M. tuberculosis isolates to the development of resistance to increasing numbers of antibiotics and may increase the ability of drug-resistant isolates to be transmitted between subjects.

* Corresponding author. Mailing address: Division of Infectious Disease, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, MSB A920C, Newark, NJ 07103. Phone: (973) 972-2179. Fax: (973) 972-0713. E-mail: allandda{at}umdnj.edu.

Antimicrobial Agents and Chemotherapy, September 2005, p. 3794-3802, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3794-3802.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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