Biochemical basis for the regulation of biosynthesis of antiparasitics by bacterial hormones
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.
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Structure of AvaR1 bound to DNA half-siteProtein Data Bank, 6WPA.
Article and author information
Author details
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.
Reviewing Editor
- Jon Clardy, Harvard Medical School, United States
Version history
- Received: April 14, 2020
- Accepted: June 6, 2020
- Accepted Manuscript published: June 8, 2020 (version 1)
- Version of Record published: July 9, 2020 (version 2)
Copyright
© 2020, Kapoor et al.
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.
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