Targeted Discovery of Cryptic Metabolites with Antiproliferative Activity.

TitleTargeted Discovery of Cryptic Metabolites with Antiproliferative Activity.
Publication TypeJournal Article
Year of Publication2022
AuthorsHan, EJ, Lee, SRak, Hoshino, S, Seyedsayamdost, MR
JournalACS Chem Biol
Volume17
Issue11
Pagination3121-3130
Date Published2022 Nov 18
ISSN1554-8937
KeywordsAnti-Bacterial Agents, Biological Products, Computational Biology, High-Throughput Screening Assays, Multigene Family
Abstract

<p>Microorganisms have provided a rich source of therapeutically valuable natural products. Recent advances in whole genome sequencing and bioinformatics have revealed immense untapped potential for new natural products in the form of silent or "cryptic" biosynthetic genes. We herein conducted high-throughput elicitor screening (HiTES) in conjunction with cytotoxicity assays against selected cancer cell lines with the goal of uncovering otherwise undetectable cryptic metabolites with antiproliferative activity. Application to facilitated identification of clavamates A and B, two bioactive metabolites with unusual structural features, as well as facile activation of a gene cluster coding for tunicamycin, which exhibited strong growth-inhibitory activity. The elicitor we identified was pleiotropic, additionally leading to the discovery of a modified, bicyclic pentapeptide natural product. Our results highlight the utility of this approach in identifying new molecules with antiproliferative activity from even overexploited microbial strains.</p>

DOI10.1021/acschembio.2c00588
Alternate JournalACS Chem Biol
PubMed ID36228140