Issue 21, 2018

Self-resistance guided genome mining uncovers new topoisomerase inhibitors from myxobacteria

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.

Graphical abstract: Self-resistance guided genome mining uncovers new topoisomerase inhibitors from myxobacteria

Supplementary files

Article information

Article type
Edge Article
Submitted
21 Mar 2018
Accepted
01 May 2018
First published
03 May 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2018,9, 4898-4908

Self-resistance guided genome mining uncovers new topoisomerase inhibitors from myxobacteria

F. Panter, D. Krug, S. Baumann and R. Müller, Chem. Sci., 2018, 9, 4898 DOI: 10.1039/C8SC01325J

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements