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The sandarazols are cryptic and structurally unique plasmid encoded toxins from a rare myxobacterium

View ORCID ProfileFabian Panter, View ORCID ProfileChantal D. Bader, View ORCID ProfileRolf Müller
doi: https://doi.org/10.1101/2020.10.06.323741
Fabian Panter
aDepartment of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, Campus E8 1, 66123 Saarbrücken, Germany
bGerman Centre for Infection Research (DZIF), Partner Site Hannover–Braunschweig, Germany
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Chantal D. Bader
aDepartment of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, Campus E8 1, 66123 Saarbrücken, Germany
bGerman Centre for Infection Research (DZIF), Partner Site Hannover–Braunschweig, Germany
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Rolf Müller
aDepartment of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, Campus E8 1, 66123 Saarbrücken, Germany
bGerman Centre for Infection Research (DZIF), Partner Site Hannover–Braunschweig, Germany
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  • For correspondence: rolf.mueller@helmholtz-hips.de
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Abstract

Soil dwelling bacteria such as myxobacteria defend themselves by using secondary metabolites to inhibit growth of competing microorganisms. In this work we describe a new plasmid found in Sandaracinus sp. MSr10575 named pSa001 spanning 209.7 kbp that harbors a cryptic secondary metabolite biosynthesis gene cluster (BGC). Activation of this BGC by homologous recombination mediated exchange of the native promoter sequence against a vanillate inducible system led to production and subsequent isolation and structure elucidation of novel secondary metabolites, the sandarazols A-G. The sandarazol structure contains intriguing features such as an α-chlorinated ketone, an epoxyketone and a (2R)-2-amino-3- (N,N-dimethylamino)-propionic acid building block. In depth investigation of the underlying biosynthetic machinery led to a concise biosynthetic model for the new compound family, including several uncommon biosynthesis steps. The chlorinated congener sandarazol C shows an IC50 value of 0.5 µM against HCT 116 cells and a MIC of 14 µM against Mycobacterium smegmatis, which points at the sandarazol’s potential function as defensive secondary metabolites or toxins. The sandara-zols’ BGC location on pSa001 is one of the very few example of large multimodular BGCs on a replicative plasmid, whose existence points at the mechanism of horizontal gene transfer events of entire multimodular BGCs to exchange chemical warfare capabilities between bacterial species.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 06, 2020.
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The sandarazols are cryptic and structurally unique plasmid encoded toxins from a rare myxobacterium
Fabian Panter, Chantal D. Bader, Rolf Müller
bioRxiv 2020.10.06.323741; doi: https://doi.org/10.1101/2020.10.06.323741
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The sandarazols are cryptic and structurally unique plasmid encoded toxins from a rare myxobacterium
Fabian Panter, Chantal D. Bader, Rolf Müller
bioRxiv 2020.10.06.323741; doi: https://doi.org/10.1101/2020.10.06.323741

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