title: Role of embB codon 306 mutations in Mycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than ethambutol resistance.
abstract: 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.
authors.affiliation: Division of Infectious Disease, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, MSB A920C, Newark, NJ 07103, USA.
authors.forename: Manzour Hernando
authors.initials: MH
authors.lastname: Hazbón
authors.forename: Miriam
authors.initials: M
authors.lastname: Bobadilla del Valle
authors.forename: Marta Inírida
authors.initials: MI
authors.lastname: Guerrero
authors.forename: Mandira
authors.initials: M
authors.lastname: Varma-Basil
authors.forename: Ingrid
authors.initials: I
authors.lastname: Filliol
authors.forename: Magali
authors.initials: M
authors.lastname: Cavatore
authors.forename: Roberto
authors.initials: R
authors.lastname: Colangeli
authors.forename: Hassan
authors.initials: H
authors.lastname: Safi
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: Amy
authors.initials: A
authors.lastname: Davidow
authors.forename: Michael
authors.initials: M
authors.lastname: Brimacombe
authors.forename: Clara Inés
authors.initials: CI
authors.lastname: León
authors.forename: Tania
authors.initials: T
authors.lastname: Porras
authors.forename: Mridula
authors.initials: M
authors.lastname: Bose
authors.forename: Fernando
authors.initials: F
authors.lastname: Chaves
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Eisenach
authors.forename: José
authors.initials: J
authors.lastname: Sifuentes-Osornio
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ponce de León
authors.forename: M Donald
authors.initials: MD
authors.lastname: Cave
authors.forename: David
authors.initials: D
authors.lastname: Alland
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001483:Base Sequence; D016000:Cluster Analysis; D004269:DNA, Bacterial / Q000235:genetics; D024881:Drug Resistance, Bacterial; D004977:Ethambutol / Q000494:pharmacology*; D005798:Genes, Bacterial / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D005810:Multigene Family; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D010802:Phylogeny
chemical_list: D000995:Antitubercular Agents; D004269:DNA, Bacterial; D004977:Ethambutol