Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones

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Abstract

Diffusible small molecule microbial hormones drastically alter the expression profiles of antibiotics and other drugs in actinobacteria. For example, avenolide (a butenolide) regulates production of avermectin, derivatives of which are used in the treatment of river blindness and other parasitic diseases. Butenolides and γ-butyrolactones control production of pharmaceutically important secondary metabolites by binding to TetR family transcriptional repressors. Here, we describe a concise, 22-step synthetic strategy for the production of avenolide. We present crystal structures of the butenolide receptor AvaR1 in isolation, and in complex with avenolide, as well as AvaR1 bound to an oligonucleotide derived from its operator. Biochemical studies guided by the co-crystal structures enable identification of 90 new actinobacteria that may be regulated by butenolides, two of which are experimentally verified. These studies provide a foundation for understanding regulation of microbial secondary metabolite production, which may be exploited for the discovery and production of novel medicines.

Data availability

Diffraction data has been deposited in the PDB under accession codes 6WP7, 6WP9 and 6WPA.

The following data sets were generated

(2020) Structure of AvaR1
Protein Data Bank, 6WP7.

https://www.rcsb.org/structure/6WP7
(2020) Structure of AvaR1 bound to avenolide
Protein Data Bank, 6WP9.

https://www.rcsb.org/structure/6WP9
(2020) Structure of AvaR1 bound to DNA half-site
Protein Data Bank, 6WPA.

https://www.rcsb.org/structure/6WPA

Article and author information

Author details

Iti Kapoor

Biochemistry, University of Illinois at Urbana-Champaign, Urbana, United States

Competing interests
The authors declare that no competing interests exist.
Philip Olivares

Department of Biochemistry, University of Illinois at Urbana-Champaign, Rockville, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3182-5884
Satish K Nair

Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, United States

For correspondence
s-nair@life.uiuc.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1790-1334

Funding

National Institutes of Health (GM131347)

Iti Kapoor

The funding agency provided support for facilities and services. The agency also provided partial salary support for all participants.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.