Coupling of the biosynthesis and export of the DNA gyrase inhibitor simocyclinone in Streptomyces antibioticus

Because most antibiotics are potentially lethal to the producing organism, there must be mechanisms to ensure that the machinery responsible for export of the mature antibiotic is in place at the time of biosynthesis. Simocyclinone D8 is a potent DNA gyrase inhibitor produced by Streptomyces antibio...

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Bibliographic Details
Published in:Molecular microbiology 2009-06, Vol.72 (6), p.1462-1474
Main Authors: Le, Tung B.K, Fiedler, Hans-Peter, den Hengst, Chris D, Ahn, Sang Kyun, Maxwell, Anthony, Buttner, Mark J
Format: Article
Language:English
Subjects:
Antibiotics
Bacterial proteins
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Bacteriology
Binding sites
Biological and medical sciences
Biosynthesis
Coumarins - metabolism
Deoxyribonucleic acid
DNA
Enzymes
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Bacterial
Genes, Bacterial
Glycosides - biosynthesis
Microbiology
Miscellaneous
Operator Regions, Genetic
Promoter Regions, Genetic
Streptomyces antibioticus
Streptomyces antibioticus - genetics
Streptomyces antibioticus - metabolism
Streptomyces lividans
Topoisomerase II Inhibitors
Transcription Initiation Site
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Summary:Because most antibiotics are potentially lethal to the producing organism, there must be mechanisms to ensure that the machinery responsible for export of the mature antibiotic is in place at the time of biosynthesis. Simocyclinone D8 is a potent DNA gyrase inhibitor produced by Streptomyces antibioticus Tü 6040. Within the simocyclinone biosynthetic cluster are two divergently transcribed genes, simR and simX, encoding proteins that resemble the TetR/TetA repressor-efflux pump pair that cause widespread resistance to clinically important tetracyclines. Engineered expression of simX from a strong, heterologous promoter conferred high level simocyclinone D8 resistance on Streptomyces lividans, showing that simX encodes a simocyclinone efflux pump. Transcription of simX is controlled by SimR, which directly represses the simX and simR promoters by binding to two operator sites in the simX-simR intergenic region. Simocyclinone D8 abolishes DNA binding by SimR, providing a mechanism that couples the biosynthesis of simocyclinone to its export. In addition, an intermediate in the biosynthetic pathway, simocyclinone C4, which is essentially inactive as a DNA gyrase inhibitor, also induces simX expression in vivo and relieves simX repression by SimR in vitro.
ISSN:0950-382X
1365-2958
DOI:10.1111/j.1365-2958.2009.06735.x