Please use this identifier to cite or link to this item: doi:10.22028/D291-28551
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Title: Self-resistance guided genome mining uncovers new topoisomerase inhibitors from myxobacteria
Author(s): Panter, Fabian
Krug, Daniel
Baumann, Sascha
Müller, Rolf
Language: English
Title: Chemical science
Volume: 9
Issue: 21
Publisher/Platform: RSC Chemical Science
Year of Publication: 2019
Publikation type: Journal Article
Abstract: There is astounding discrepancy between the genome-inscribed production capacity and the set of known secondary metabolite classes from many microorganisms as detected under laboratory cultivation conditions. Genome-mining techniques are meant to fill this gap, but in order to favor discovery of structurally novel as well as bioactive compounds it is crucial to amend genomics-based strategies with selective filtering principles. In this study, we followed a self-resistance guided approach aiming at the discovery of inhibitors of topoisomerase, known as valid target in both cancer and antibiotic therapy. A common host self-defense mechanism against such inhibitors in bacteria is mediated by so-called pentapeptide repeat proteins (PRP). Genes encoding the biosynthetic machinery for production of an alleged topoisomerase inhibitor were found on the basis of their collocation adjacent to a predicted PRP in the genome of the myxobacterium Pyxidicoccus fallax An d48, but to date no matching compound has been reported from this bacterium. Activation of this peculiar polyketide synthase type-II gene cluster in the native host as well as its heterologous expression led to the structure elucidation of new natural products that were named pyxidicyclines and provided an insight into their biosynthesis. Subsequent topoisomerase inhibition assays showed strong affinity to - and inhibition of - unwinding topoisomerases such as E. coli topoisomerase IV and human topoisomerase I by pyxidicyclines as well as precise selectivity, since E. coli topoisomerase II (gyrase) was not inhibited at concentrations up to 50 μg ml-1.
DOI of the first publication: 10.1039/c8sc01325j
Link to this record: hdl:20.500.11880/27684
ISSN: 2041-6520
Date of registration: 6-Sep-2019
Faculty: NT - Naturwissenschaftlich- Technische Fakultät
Department: NT - Pharmazie
Professorship: NT - Prof. Dr. Rolf Müller
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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