Resistance to macrolides, lincosamides and streptogramin type B antibiotics due to a mutation in an rRNA operon of Streptomyces ambofaciens.

Abstract

Streptomyces ambofaciens produces spiramycin, a macrolide antibiotic and expresses an inducible resistance to macrolides, lincosamides and streptogramin B antibiotics (MLS). From a mutant of S.ambofaciens exhibiting a constitutive MLS resistance phenotype a resistance determinant was cloned on a low copy number vector (pIJ61) through its expression in Streptomyces lividans. Further characterization has shown that this determinant corresponded to a mutant rRNA operon with a mutation in the 23S rRNA gene. In different organisms, mutations leading to MLS resistance have been located at a position corresponding to the adenine 2058 of Escherichia coli 23S rRNA. In the 23S rRNA from S.ambofaciens a similar position for the mutation has been postulated and DNA sequencing of this region has shown an adenine to guanine transition at a position corresponding to 2058. S.ambofaciens possesses four rRNA operons which we have cloned. In Streptomyces, contrary to other bacteria, a mutation in one among several rRNA operons confers a selectable MLS resistance phenotype. Possible reasons for this difference are discussed.

Macrolide Resistance Conferred by Base Substitutions in 23S rRNA

“…Mutations that have been conclusively demonstrated to exhibit the MLS B phenotype are A2058U in E. coli (120), A2058C/G/U in H. pylori (148), A2058G in Propionibacterium spp. (111), and A2058G in Streptomyces ambofaciens (98). However, the present indications make it judicious to assume that the 2058G mutation would confer true MLS B resistance in any bacterium with a low rrn copy number.…”

The role of ribosomal RNAs in macrolide resistance

“…However, in these studies, the genomic context of the mutated gene was not investigated, i.e. it was not determined whether the mutated gene was indeed present in the context of three wild-type rRNA operons or whether gene conversion processes had taken place (Pernodet et al, 1988).…”

Chalcomycin Biosynthesis Gene Cluster from Streptomyces bikiniensis : Novel Features of an Unusual Ketolide Produced through Expression of the chm Polyketide Synthase in Streptomyces fradiae

“…Chalcomycin was determined to have modest antibiotic activity against gram-positive organisms: the MIC at which 50% of 11 susceptible Staphylococcus aureus strains were inhibited was 0.19 g/ml, with a range of 0.05 to 0.78 g/ml; the MICs for two susceptible Streptococcus pyogenes strains were 0.19 and 0.78 g/ml (11). Although its precise mechanism of action was not determined, chalcomycin was found to inhibit protein synthesis and to exhibit cross-resistance with a number of macrolides; hence, chalcomycin was thought to act in the same manner as tylosin (29). In addition, whereas macrolides are not known to inhibit tRNA synthetases, chalcomycin was shown to inhibit the incorporation of [ 14 C]glycine into glycyltRNA in S. aureus (18).…”