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Genomics-driven discovery of a novel glutarimide antibiotic from Burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism
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Challis, Gregory L., Nakou, Ioanna, Jenner, Matthew, Dashti, Yousef, Romero-Canelón, Isolda, Masschelein, Joleen and Mahenthiralingam, Eshwar (2020) Genomics-driven discovery of a novel glutarimide antibiotic from Burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism. Angewandte Chemie International Edition, 59 (51). pp. 23145-23153. doi:10.1002/anie.202009007 ISSN 1433-7851.
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WRAP-genomics-driven-discovery-novel-glutarimide-antibiotic-Burkholderia-gladioli-reveals-unusual-polyketide-synthase-chain-release-mechanism-Challis-2020.pdf - Accepted Version - Requires a PDF viewer. Download (1673Kb) | Preview |
Official URL: https://doi.org/10.1002/anie.202009007
Abstract
A gene cluster encoding a cryptic trans ‐acyl transferase polyketide synthase (PKS) was identified in the genomes of Burkholderia gladioli BCC0238 and BCC1622, both isolated from the lungs of cystic fibrosis patients. Bioinfomatics analyses indicated the PKS assembles a novel member of the glutarimide class of antibiotics, hitherto only isolated from Streptomyces species. Screening of a range of growth parameters enabled gladiostatin, the metabolic product of the PKS, to be identified. NMR spectroscopic analysis revealed that gladiostatin, which has promising activity against several human cancer cell lines and inhibits tumor cell migration, contains an unusual 2‐acyl‐4‐hydroxy‐3‐methylbutenolide in addition to the glutarimide pharmacophore. An AfsA‐like domain at the C‐terminus of the PKS was shown to catalyze condensation of 3‐ketothioesters with dihydroxyacetone phosphate, indicating it plays a key role in polyketide chain release and butenolide formation.
Item Type: | Journal Article | ||||||||||||||||||||||||
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Subjects: | Q Science > QD Chemistry R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Antineoplastic agents -- Research, Antibiotics -- Synthesis, Antineoplastic antibiotics, Enzymology | ||||||||||||||||||||||||
Journal or Publication Title: | Angewandte Chemie International Edition | ||||||||||||||||||||||||
Publisher: | Wiley - V C H Verlag GmbH & Co. KGaA | ||||||||||||||||||||||||
ISSN: | 1433-7851 | ||||||||||||||||||||||||
Official Date: | 14 December 2020 | ||||||||||||||||||||||||
Dates: |
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Volume: | 59 | ||||||||||||||||||||||||
Number: | 51 | ||||||||||||||||||||||||
Page Range: | pp. 23145-23153 | ||||||||||||||||||||||||
DOI: | 10.1002/anie.202009007 | ||||||||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||||||||
Reuse Statement (publisher, data, author rights): | This is the peer reviewed version of the following article: Challis, G., Nakou, I..T., Jenner, M., Dashti, Y., Romero-Canelón, I., Masschelein, J. and Mahenthiralingam, E. (2020), Genomics‐driven discovery of a novel glutarimide antibiotic from Burkholderia gladioli reveals an unusual polyketide synthase chain release mechanism. Angew. Chem. Int. Ed.. Accepted Author Manuscript. doi:10.1002/anie.202009007, which has been published in final form at https://doi.org/10.1002/anie.202009007. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. | ||||||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||
Date of first compliant deposit: | 23 September 2020 | ||||||||||||||||||||||||
Date of first compliant Open Access: | 12 September 2021 | ||||||||||||||||||||||||
RIOXX Funder/Project Grant: |
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