Role of embB Codon 306 Mutations in Mycobacterium tuberculosis Revisited: a Novel Association with Broad Drug Resistance and IS 6110 Clustering Rather than Ethambutol Resistance

Abstract

ABSTRACT Mutations at position 306 of embB ( embB 306) have been proposed as a marker for ethambutol resistance in Mycobacterium tuberculosis ; however, recent reports of embB 306 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 embB 306 mutations, drug resistance patterns, and major genetic group. One hundred isolates (10%) contained a mutation in embB 306; however, only 55 of these mutants were ethambutol resistant. Mutations in embB 306 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 embB 306 mutations and resistance to increasing numbers of drugs was highly significant ( P < 0.001 for trend). We examined the association between embB 306 mutations and IS 6110 clustering (as a proxy for transmission) among all drug-resistant isolates. Mutations in embB 306 were significantly associated with clustering by univariate analysis (odds ratio, 2.44; P = 0.004). In a multivariate model that also included mutations in katG 315, katG 463, gyrA 95, and kasA 269, only mutations in embB 306 (odds ratio, 2.14; P = 0.008) and katG 315 (odds ratio, 1.99; P = 0.015) were found to be independently associated with clustering. In conclusion, embB 306 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.