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Appl Environ Microbiol. 2019 Nov 15. pii: AEM.01876-19. doi: 10.1128/AEM.01876-19. [Epub ahead of print]

In situ activation and heterologous production of a cryptic lantibiotic from a plant-ant derived Saccharopolyspora species.

Author information

1
Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
2
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
3
Department of Organismic and Evolutionary Biology, Harvard University, Cambridge MA 02138, USA.
4
Mpala Research Centre, P O Box 555, Nanyuki, 10400 Kenya.
5
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK barrie.wilkinson@jic.ac.uk m.hutchings@uea.ac.uk.
6
Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK barrie.wilkinson@jic.ac.uk m.hutchings@uea.ac.uk.

Abstract

Most clinical antibiotics are derived from actinomycete natural products discovered at least 60 years ago. However, the repeated rediscovery of known compounds led the pharmaceutical industry to largely discard microbial natural products as a source of new chemical diversity. Recent advances in genome sequencing have revealed that these organisms have the potential to make many more NPs than previously thought. Approaches to unlock NP biosynthesis by genetic manipulation of strains, by the application of chemical genetics, or by microbial co-cultivation have resulted in the identification of new antibacterial compounds. Concomitantly, intensive exploration of coevolved ecological niches, such as insect-microbe defensive symbioses, has revealed these to be a rich source of chemical novelty. Here we report the new lanthipeptide antibiotic kyamicin, which was generated through the activation of a cryptic biosynthetic gene cluster identified by genome mining Saccharopolyspora species found in the obligate domatia-dwelling ant Tetraponera penzigi of the ant plant Vachellia drepanolobium Transcriptional activation of this silent gene cluster was achieved by ectopic expression of a pathway specific activator under the control of a constitutive promoter. Subsequently, a heterologous production platform was developed which enabled the purification of kyamicin for structural characterisation and bioactivity determination. This strategy was also successful for the production of lantibiotics from other genera, paving the way for a synthetic heterologous expression platform for the discovery of lanthipeptides that are not detected under laboratory conditions or that are new to nature.Importance The discovery of novel antibiotics to tackle the growing threat of antimicrobial resistance is impeded by difficulties in accessing the full biosynthetic potential of microorganisms. The development of new tools to unlock the biosynthesis of cryptic bacterial natural products will greatly increase the repertoire of natural product scaffolds. Here we report a strategy for the ectopic expression of pathway specific positive regulators that can be rapidly applied to activate the biosynthesis of cryptic lanthipeptide biosynthetic gene clusters. This allowed the discovery of a new lanthipeptide antibiotic directly from the native host and via heterologous expression.

PMID:
31732571
DOI:
10.1128/AEM.01876-19
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