THIOLACTOMYCIN RESISTANCE IN ESCHERICHIA-COLI IS ASSOCIATED WITH THE MULTIDRUG-RESISTANCE EFFLUX PUMP ENCODED BY EMRAB

Thiolactomycin (TLM) and cerulenin are antibiotics that block Escheric hia coli growth by inhibiting fatty acid biosynthesis at the beta-keto acyl-acyl carrier protein synthase I step. Both TLM and cerulenin trig ger the accumulation of intracellular malonyl-coenzyme A coincident wi th growth inhibition, and the overexpression of synthase I protein con fers resistance to both antibiotics. Strain CDM5 was derived as a TLM- resistant mutant but remained sensitive to cerulenin. TLM neither indu ced malonyl-coenzyme A accumulation nor blocked fatty acid production in vivo; however, the fatty acid synthase activity in extracts from st rain CDM5 was sensitive to TLM inhibition. The TLM resistance gene in strain CDM5 was mapped to 57.5 min of the chromosome and was an allele of the emrB gene. Disruption of the emrB gene converted strain CDM5 t o a TLM-sensitive strain, and the overexpression of the emrAB operon c onferred TLM resistance to sensitive strains. Thus, activation of the emr efflux pump is the mechanism for TLM resistance in strain CDM5.