Total Synthesis of Xanthoangelol B and Its Various Fragments: Toward Inhibition of Virulence Factor Production of Staphylococcus aureus

Pushpak Mizar, Rekha Arya, Truc Kim, Soyoung Cha, Kyoung Seok Ryu, Won Sik Yeo, Taeok Bae, Dae Wook Kim, Ki Hun Park, Kyeong Kyu Kim, Seung Seo Lee

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

As an alternative strategy to fight antibiotic resistance, two-component systems (TCSs) have emerged as novel targets. Among TCSs, master virulence regulators that control the expression of multiple virulence factors are considered as excellent antivirulence targets. In Staphylococcus aureus, virulence factor expression is tightly regulated by a few master regulators, including the SaeRS TCS. In this study, we used a SaeRS GFP-reporter system to screen natural compound inhibitors of SaeRS, and identified xanthoangelol B 1, a prenylated chalcone from Angelica keiskei as a hit. We have synthesized 1 and its derivative PM-56 and shown that 1 and PM-56 both had excellent inhibitory potency against the SaeRS TCS, as demonstrated by various in vitro and in vivo experiments. As a mode of action, 1 and PM-56 were shown to bind directly to SaeS and inhibit its histidine kinase activity, which suggests a possibility of a broad spectrum inhibitor of histidine kinases.

Original languageEnglish (US)
Pages (from-to)10473-10487
Number of pages15
JournalJournal of Medicinal Chemistry
Volume61
Issue number23
DOIs
StatePublished - Dec 13 2018

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Mizar, P., Arya, R., Kim, T., Cha, S., Ryu, K. S., Yeo, W. S., Bae, T., Kim, D. W., Park, K. H., Kim, K. K., & Lee, S. S. (2018). Total Synthesis of Xanthoangelol B and Its Various Fragments: Toward Inhibition of Virulence Factor Production of Staphylococcus aureus. Journal of Medicinal Chemistry, 61(23), 10473-10487. https://doi.org/10.1021/acs.jmedchem.8b01012