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Identifying natural-product antibiotics through induced expression of biosynthetic gene clusters

Induced expression of biosynthetic gene clusters isolated from environmental DNA could help generate new antibiotic leads. Many biosynthetic gene clusters that have been identified by sequencing environmental DNA samples are not well expressed in Escherichia coli systems. To improve expression, transcriptional regulators within sequenced biosynthetic gene clusters were identified, cloned into a plasmid and then coexpressed in Streptomyces albus along with the corresponding gene cluster they were predicted to control. Screening and fractionation of these S. albus cultures identified a tetracyclic antibiotic, tetarimycin A, with an MIC of 0.78 mg/ml against methicillin-resistant Staphylococcus aureus (MRSA). Next steps include scaling this approach to look at a larger number of environmental DNA-derived gene clusters arising from a more diverse set of environments.

SciBX 5(49); doi:10.1038/scibx.2012.1293
Published online Dec. 20, 2012

Patent and licensing status undisclosed

Kallifidas, D. et al. J. Am. Chem. Soc.; published online Nov. 16, 2012;
Contact: Sean F. Brady, The Rockefeller University, New York, N.Y.