Sorangicin A, a macrolide polyether antibiotic and the ansamycin antibiotic rifampicin inhibit DNA-dependentRNApolymerase to a similar extent. Resistance to sorangicin A is due to a mutation in the RNApolymerase which renders the enzyme less sensitive. Parallel investigations with rifampicin revealed partial cross-resistance, which was more marked in sorangicin A-resistant mutants than in rifampicin-resistant mutants. Sorangicin A is a new type of macrolide polyether antibiotic isolated from the gliding bacterium Sorangium cellulosum. Its antimicrobial properties are similar to those of the ansamycin antibiotic rifampicin. Sorangicin A is highly active against Gram-positive bacteria (MIC<0.01~2^g/ml) and less so against Gram-negative bacteria (MIC 2~>32^g/ml). The drug also resembles rifampicin in its mechanism of action, since it specifically affects bacterial DNA-dependent RNApolymerase1~3). The chemical structures of the two drugs are, however, quite different. The aim of the present work was to analyze the mechanismof resistance of Escherichia coli to sorangicin A and to compare it to the resistance against rifampicin.