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Antimicrobial Agents and Chemotherapy, August 2006, p. 2640-2649, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00112-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis{dagger}

Manzour Hernando Hazbón,1 Michael Brimacombe,2 Miriam Bobadilla del Valle,3 Magali Cavatore,1 Marta Inírida Guerrero,4,{ddagger} Mandira Varma-Basil,5 Helen Billman-Jacobe,6 Caroline Lavender,7 Janet Fyfe,7 Lourdes García-García,8 Clara Inés León,4,{ddagger} Mridula Bose,5 Fernando Chaves,9 Megan Murray,10 Kathleen D. Eisenach,11 José Sifuentes-Osornio,3 M. Donald Cave,11 Alfredo Ponce de León,3 and David Alland1*

Division of Infectious Disease, Department of Medicine, and the Ruy V. Lourenço Center for the Study of Emerging and Re-Emerging Pathogens, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103,1 Department of Preventive Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103,2 Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico,3 Grupo de Micobacterias, Subdirección de Investigación, Instituto Nacional de Salud, Bogotá, Colombia,4 Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110007, India,5 Department of Microbiology and Immunology, University of Melbourne, Royal Parade, Parkville, Victoria 3010, Australia,6 Victorian Mycobacterium Reference Laboratory, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria 3051, Australia,7 Instituto Nacional de Salud Pública, Mexico City, Mexico,8 Servicio de Microbiología, Hospital Universitario Doce de Octubre, 28041 Madrid, Spain,9 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115,10 Central Arkansas Veterans Healthcare System (CAVHS), Departments of Pathology, Microbiology-Immunology, and Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205,11

Received 26 January 2006/ Returned for modification 21 February 2006/ Accepted 4 May 2006

The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.

* 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.

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

{ddagger} Present address: Unidad de Genética, Facultad de Medicina, Universidad del Rosario, Bogotá, Colombia.

Antimicrobial Agents and Chemotherapy, August 2006, p. 2640-2649, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00112-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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