Role of embB codon 306 mutations in Mycobacterium tuberculosis revisited: a novel association with broad drug resistance and IS6110 clustering rather than ethambutol resistance.
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.
Hazbón
Manzour Hernando
MH
Division of Infectious Disease, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, MSB A920C, Newark, NJ 07103, USA.
Bobadilla del Valle
Miriam
M
Guerrero
Marta Inírida
MI
Varma-Basil
Mandira
M
Filliol
Ingrid
I
Cavatore
Magali
M
Colangeli
Roberto
R
Safi
Hassan
H
Billman-Jacobe
Helen
H
Lavender
Caroline
C
Fyfe
Janet
J
García-García
Lourdes
L
Davidow
Amy
A
Brimacombe
Michael
M
León
Clara Inés
CI
Porras
Tania
T
Bose
Mridula
M
Chaves
Fernando
F
Eisenach
Kathleen D
KD
Sifuentes-Osornio
José
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Ponce de León
Alfredo
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Cave
M Donald
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Alland
David
D
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
D000995:Antitubercular Agents; D004269:DNA, Bacterial; D004977:Ethambutol