Discovery of Bioactive Metabolites by Acidic Stress to a Geldanamycin Producer, Streptomyces samsunensis

Jin Won Choi, Yeonhee Lee, Jaekyeong Kim, Haeun Kwon, Stephen T. Deyrup, Jin Woo Lee, Dongho Lee, Hahk Soo Kang, Hwangsoo Joo, Sang Hee Shim

Research output: Contribution to journalArticlepeer-review

Abstract

In an effort to activate silent biosynthetic gene clusters, Streptomyces samsunensis DSM42010, a producer of geldanamycin, was cultured at four different pHs (4.5, 5.4, 6.6, and 7.4). An acidic culture condition (pH 5.4) was selected for a chemical investigation since S. samsunensis showed a different metabolic profile compared to when it was cultured under other conditions. Seven new (1-7) and four known (8-11) compounds were isolated from these cultures. The structures of the isolated compounds were determined by spectroscopic techniques and chemical derivatization. Relative and absolute configurations of the new compounds (1-5) were established using JBCA, PGME method, advanced Marfey’s method, modified Mosher’s method, and comparison of observed and calculated ECD data. Interestingly, compounds 1-3 were truncated versions of geldanamycin, and compound 4 was also deduced to originate from geldanamycin. Compound 5 was composed of 3-methyltyrosine and 6-hydroxy-2,4-hexadienoic acid connected through an amide bond. Compounds 6 and 7 were dihydrogenated forms of geldanamycin with a hydroxy substitution. It is possible that culturing this strain under acidic conditions interfered to some degree with the geldanamycin polyketide synthase, leading to production of truncated versions as well as analogues of geldanamycin. Compounds 1, 8, and 9 showed significant antivirulence activity, inhibiting production of α-toxin by methicillin-resistant Staphylococcus aureus without growth attenuation and global regulatory inhibition; compounds 1, 8, and 9 may become promising α-toxin-specific antivirulence leads with less risk of resistance development.

Original languageEnglish
Pages (from-to)947-957
Number of pages11
JournalJournal of Natural Products
Volume86
Issue number4
DOIs
Publication statusPublished - 2023 Apr 28

Bibliographical note

Funding Information:
This research was supported by the National Research Foundation of Korea (NRF-2016R1A6A1A03007648, NRF-2019R1A4A1020626, and NRF-2021R1A2C1004958).

Publisher Copyright:
© 2023 American Chemical Society and American Society of Pharmacognosy.

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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