Identifying producers of antibacterial compounds by screening for antibiotic resistance

Abstract

Microbially derived natural products are major sources of antibiotics and other medicines, but discovering new antibiotic scaffolds and increasing the chemical diversity of existing ones are formidable challenges. We have designed a screen to exploit the self-protection mechanism of antibiotic producers to enrich microbial libraries for producers of selected antibiotic scaffolds. Using resistance as a discriminating criterion we increased the discovery rate of producers of both glycopeptide and ansamycin antibacterial compounds by several orders of magnitude in comparison with historical hit rates. Applying a phylogeny-based screening filter for biosynthetic genes enabled the binning of producers of distinct scaffolds and resulted in the discovery of a glycopeptide antibacterial compound, pekiskomycin, with an unusual peptide scaffold. This strategy provides a means to readily sample the chemical diversity available in microbes and offers an efficient strategy for rapid discovery of microbial natural products and their associated biosynthetic enzymes.

Isolation and antimicrobial activities of actinobacteria closely associated with liquorice plants Glycyrrhiza glabra L. and Glycyrrhiza inflate BAT. in Xinjiang, China

“…However, since the antibiotic-producing strains must be resistant to the compounds they produce, Thaker et al (2013) applied antibiotic resistance in screening actinobacteria from soil, and they successfully isolated a strain producing a novel antibacterial glycopeptide. Many of the plant products applied in traditional medicine have antimicrobial properties.…”

Antibiotic Resistance Mechanisms Inform Discovery: Identification and Characterization of a Novel Amycolatopsis Strain Producing Ristocetin

“…Thaker et al recently reported the discovery of the novel glycopeptide pekiskomycin using growth in the presence of vancomycin as an initial screen to enrich for glycopeptide-producing strains derived from soil samples (44). A significant proportion of the vancomycin-resistant strains (89/100 strains) isolated in this way did not contain glycopeptide biosynthetic clusters, however, and it was necessary to include an additional PCR-based screen to identify those that did.…”

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production

“…Following these findings, the synthetic derivative Cl-ARC was used for the stronger elicitation of BGCs encoding molecules at a low abundance in a panel of fifty Actinomycete strains. [65] This resulted in the identification of several CI-ARC-induced compounds including oxohygrolidin from Streptomyces ghanaensis, not previously known to produce this molecule. [66] Furthermore, based on bioactivity-guided assays, it was shown that while the extracts of the elicitor-treated S. ghanaensis failed to provide detectable inhibition, purified oxohydrolidin displayed activity against S. cerevisiae Y7092.…”