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. 2010 May;54(5):1684-92.
doi: 10.1128/AAC.01406-09. Epub 2010 Feb 22.

Involvement of the beta subunit of RNA polymerase in resistance to streptolydigin and streptovaricin in the producer organisms Streptomyces lydicus and Streptomyces spectabilis

Marina Sánchez-Hidalgo  1 , Luz Elena Núñez, Carmen Méndez, José A Salas
Affiliations

Involvement of the beta subunit of RNA polymerase in resistance to streptolydigin and streptovaricin in the producer organisms Streptomyces lydicus and Streptomyces spectabilis

Marina Sánchez-Hidalgo et al. Antimicrob Agents Chemother. 2010 May.

Abstract

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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Figures

FIG. 1.
FIG. 1.
Structures of streptolydigin and streptovaricin.
FIG. 2.
FIG. 2.
Sequence alignments of RpoB rif regions from S. lydicus, S. spectabilis, and other Streptomyces strains. Rifampin resistance clusters (I, II, and III) and streptolydigin resistance motifs (Stl1 and Stl2) are indicated. Asterisks and circles indicate mutagenized residues in S. lydicus and S. spectabilis rpoB, respectively.
FIG. 3.
FIG. 3.
Scheme representing the construction of chimeric RpoB subunits.
FIG. 4.
FIG. 4.
Streptolydigin binding sites in modeled structures of wild-type (A) and mutated (B) RpoB (dark gray) and RpoC (light gray) subunits from S. lydicus NRRL 2433 in the presence of streptolydigin (STL). The following regions that interact with streptolydigin are indicated: Stl1, Stl2, bridge helix (BH), and trigger loop (TL). Mutated residues are shown.
FIG. 5.
FIG. 5.
Rifampin binding sites in modeled structures of wild-type (A) and mutated (B) RpoB from S. spectabilis NRRL 2494 in the presence of rifampin (RIF). Clusters I, II, and III (rif region) and mutated residues are indicated. Hydrogen bonds are shown as dashed lines.
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