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

Manzour Hernando Hazbón; Michael Brimacombe; Miriam Bobadilla del Valle; Magali Cavatore; Marta Inírida Guerrero; Mandira Varma-Basil; Helen Billman-Jacobe; Caroline Lavender; Janet Fyfe; Lourdes García-García; Clara Inés León; Mridula Bose; Fernando Chaves; Megan Murray; Kathleen D Eisenach; José Sifuentes-Osornio; M. Donald Cave; Alfredo Ponce de León; David Alland

doi:10.1128/AAC.00112-06

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

Journal article

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

Manzour Hernando Hazbón, Michael Brimacombe, Miriam Bobadilla del Valle, Magali Cavatore, Marta Inírida Guerrero, Mandira Varma-Basil, Helen Billman-Jacobe, Caroline Lavender, Janet Fyfe, Lourdes García-García, …

Antimicrobial agents and chemotherapy, Vol.50(8), pp.2640-2649

08/2006

DOI: https://doi.org/10.1128/AAC.00112-06

PMCID: PMC1538650

PMID: 16870753

Abstract

Mechanisms of Resistance

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 katG 315 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 katG 315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG 315 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.

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Title: Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis
Creators: Manzour Hernando Hazbón - 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
Michael Brimacombe - 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
Miriam Bobadilla del Valle - 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
Magali Cavatore - 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
Marta Inírida Guerrero - 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
Mandira Varma-Basil - 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
Helen Billman-Jacobe - 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
Caroline Lavender - 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
Janet Fyfe - 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
Lourdes García-García - 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
Clara Inés León - 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
Mridula Bose - 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
Fernando Chaves - 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
Megan Murray - 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
Kathleen D Eisenach - 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
José Sifuentes-Osornio - 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
M. Donald Cave - 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
Alfredo Ponce de León - 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
David Alland - 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
Publication Details: Antimicrobial agents and chemotherapy, Vol.50(8), pp.2640-2649
Date published: 08/2006
Publisher: American Society for Microbiology
Academic Unit: Medicine - Infectious Diseases (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031654459604646