Targeted Discovery of Cryptic Metabolites with Antiproliferative Activity.

Publication Year
2022

Type

Journal Article
Abstract

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.

Journal
ACS Chem Biol
Volume
17
Issue
11
Pages
3121-3130
Date Published
2022 Nov 18
ISSN Number
1554-8937
Alternate Journal
ACS Chem Biol
PMID
36228140