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Open AccessReview

Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis

1
School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK
2
Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK
*
Authors to whom correspondence should be addressed.
Antibiotics 2019, 8(2), 83; https://doi.org/10.3390/antibiotics8020083
Received: 31 May 2019 / Revised: 10 June 2019 / Accepted: 14 June 2019 / Published: 18 June 2019
(This article belongs to the Special Issue Mechanism and Regulation of Antibiotic Synthesis in Streptomyces)
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Abstract

Discovering new antibiotics is vital to combat the growing threat of antimicrobial resistance. Most currently used antibiotics originate from the natural products of actinomycete bacteria, particularly Streptomyces species, that were discovered over 60 years ago. However, genome sequencing has revealed that most antibiotic-producing microorganisms encode many more natural products than previously thought. Biosynthesis of these natural products is tightly regulated by global and cluster situated regulators (CSRs), most of which respond to unknown environmental stimuli, and this likely explains why many biosynthetic gene clusters (BGCs) are not expressed under laboratory conditions. One approach towards novel natural product discovery is to awaken these cryptic BGCs by re-wiring the regulatory control mechanism(s). Most CSRs bind intergenic regions of DNA in their own BGC to control compound biosynthesis, but some CSRs can control the biosynthesis of multiple natural products by binding to several different BGCs. These cross-cluster regulators present an opportunity for natural product discovery, as the expression of multiple BGCs can be affected through the manipulation of a single regulator. This review describes examples of these different mechanisms, including specific examples of cross-cluster regulation, and assesses the impact that this knowledge may have on the discovery of novel natural products. View Full-Text
Keywords: Secondary metabolism; regulation; biosynthesis; antibiotics Secondary metabolism; regulation; biosynthesis; antibiotics
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McLean, T.C.; Wilkinson, B.; Hutchings, M.I.; Devine, R. Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis. Antibiotics 2019, 8, 83.

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