title: Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis.
abstract: 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.
authors.affiliation: Division of Infectious Disease, Department of Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
authors.forename: Manzour Hernando
authors.initials: MH
authors.lastname: Hazbón
authors.forename: Michael
authors.initials: M
authors.lastname: Brimacombe
authors.forename: Miriam
authors.initials: M
authors.lastname: Bobadilla del Valle
authors.forename: Magali
authors.initials: M
authors.lastname: Cavatore
authors.forename: Marta Inírida
authors.initials: MI
authors.lastname: Guerrero
authors.forename: Mandira
authors.initials: M
authors.lastname: Varma-Basil
authors.forename: Helen
authors.initials: H
authors.lastname: Billman-Jacobe
authors.forename: Caroline
authors.initials: C
authors.lastname: Lavender
authors.forename: Janet
authors.initials: J
authors.lastname: Fyfe
authors.forename: Lourdes
authors.initials: L
authors.lastname: García-García
authors.forename: Clara Inés
authors.initials: CI
authors.lastname: León
authors.forename: Mridula
authors.initials: M
authors.lastname: Bose
authors.forename: Fernando
authors.initials: F
authors.lastname: Chaves
authors.forename: Megan
authors.initials: M
authors.lastname: Murray
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Eisenach
authors.forename: José
authors.initials: J
authors.lastname: Sifuentes-Osornio
authors.forename: M Donald
authors.initials: MD
authors.lastname: Cave
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ponce de León
authors.forename: David
authors.initials: D
authors.lastname: Alland
mesh_terms: D000483:Alleles; D000904:Antibiotics, Antitubercular / Q000494:pharmacology; D000995:Antitubercular Agents / Q000494:pharmacology*; D005075:Biological Evolution; D004252:DNA Mutational Analysis; D004269:DNA, Bacterial / Q000235:genetics; D021901:DNA, Intergenic / Q000235:genetics; D004977:Ethambutol / Q000494:pharmacology; D017353:Gene Deletion; D005798:Genes, Bacterial; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D016366:Open Reading Frames; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012293:Rifampin / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D013307:Streptomycin / Q000494:pharmacology; D018088:Tuberculosis, Multidrug-Resistant / Q000235:genetics*
chemical_list: D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D004269:DNA, Bacterial; D021901:DNA, Intergenic; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin; D013307:Streptomycin