Assembling the glycopeptide antibiotic scaffold: The biosynthesis of A47934 from Streptomyces toyocaensis NRRL15009.
The glycopeptide antibiotics vancomycin and teicoplanin are vital components of modern anti-infective chemotherapy exhibiting outstanding activity against Gram-positive pathogens including members of the genera Streptococcus, Staphylococcus, and Enterococcus. These antibiotics also provide fascinating examples of the chemical and associated biosynthetic complexity exploitable in the synthesis of natural products by actinomycetes group of bacteria. We report the sequencing and annotation of the biosynthetic gene cluster for the glycopeptide antibiotic from Streptomyces toyocaensis NRRL15009, the first complete sequence for a teicoplanin class glycopeptide. The cluster includes 34 ORFs encompassing 68 kb and includes all of the genes predicted to be required to synthesize and regulate its biosynthesis. The gene cluster also contains ORFs encoding enzymes responsible for glycopeptide resistance. This role was confirmed by insertional inactivation of the d-Ala-d-lactate ligase, vanAst, which resulted in the predicted -sensitive phenotype and impaired antibiotic biosynthesis. These results provide increased understanding of the biosynthesis of these complex natural products.
Pootoolal
Jeff
J
Antimicrobial Research Centre, Department of Biochemistry, McMaster University, Hamilton, ON, Canada L8N 3Z5.
Thomas
Michael G
MG
Marshall
C Gary
CG
Neu
John M
JM
Hubbard
Brian K
BK
Walsh
Christopher T
CT
Wright
Gerard D
GD
D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D012310:Ristocetin / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000737:chemistry; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D017931:DNA Primers; D012310:Ristocetin; C051056:antibiotic A 47934