Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 54, Issue 5, Pages 1684-1692Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01406-09
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Funding
- Spanish Ministry of Science and Innovation [BFU2006-00404]
- Red Tematica de Investigacion Cooperativa de Centros de Cancer (Ministry of Health) [ISCIII-RETIC RD06/0020/0026]
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Streptomyces lydicus NRRL2433 and S. spectabilis NRRL2494 produce two inhibitors of bacterial RNA polymerase: the 3-acyltetramic acid streptolydigin and the naphthalenic ansamycin streptovaricin, respectively. Both strains are highly resistant to their own antibiotics. Independent expression of the S. lydicus and S. spectabilis rpoB and rpoC genes, encoding the beta- and beta'-subunits of RNA polymerase, respectively, in S. albus showed that resistance is mediated by rpoB, with no effect of rpoC. Within the beta-subunit, resistance was confined to an amino acid region harboring the rif region. Comparison of the beta-subunit amino acid sequences of this region from the producer strains and those of other streptomycetes and site-directed mutagenesis of specific differential residues located in it (L485 and D486 in S. lydicus and N474 and S475 in S. spectabilis) showed their involvement in streptolydigin and streptovaricin resistance. Other amino acids located close to the Stl pocket in the S. lydicus beta-subunit (L555, F593, and M594) were also found to exert influence on streptolydigin resistance.
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