ROLE OF EMBB IN NATURAL AND ACQUIRED-RESISTANCE TO ETHAMBUTOL IN MYCOBACTERIA

The mycobacterial embCAB operon encodes arabinosyl transferases, putat ive targets of the antimycobacterial agent ethambutol (EMB). Mutations in embB lead to resistance to EMB in Mycobacterium tuberculosis, The basis for natural, intrinsic resistance to EMB in nontuberculous mycob acteria (NTM) is not known; neither is the practical implication of re sistance to EMB in the absence of embB mutations in M. tuberculosis we ll understood, The conserved embB resistance-determining region (ERDR) of a collection of 13 strains of NTM and 12 EMB-resistant strains of M, tuberculosis was investigated, Genotypes were correlated with drug susceptibility phenotypes, High level natural resistance to EMB (MIC, greater than or equal to 64 mu g/ml) was associated with a variant ami no acid motif in the ERDR of M, abscessus, M. chelonae, and M. leprae, Transfer of the M. abscessus emb allele to M, smegmatis resulted in a 500-fold increase in the MICs, In M. tuberculosis, embB mutations wer e associated with MICs of greater than or equal to 20 mu g/ml while re sistance not associated with an ERDR mutation generally resulted in MI Cs of less than or equal to 10 mu g/ml. These data further support the notion that the emb region determines intrinsic and acquired resistan ce to EMB and might help in the reassessment of the current recommenda tions for the screening and treatment of infections with EMB-resistant M, tuberculosis and NTM.