The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

Total synthesis of xanthoangelol B and its various fragments: towards inhibition of virulence factor production of Staphylococcus aureus

Total synthesis of xanthoangelol B and its various fragments: towards inhibition of virulence factor production of Staphylococcus aureus
Total synthesis of xanthoangelol B and its various fragments: towards inhibition of virulence factor production of Staphylococcus aureus

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 anti-virulence 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.

Journal Article
0022-2623
10473–10487
Mizar, Pushpak
631b688c-b7fb-41d7-8038-9fb48ef935c7
Arya, Rekha
4e1916f3-7fab-4f7f-b22a-ce84d73dd1da
Kim, Truc
64fff945-d3dc-4145-b714-d76a7024b786
Cha, Soyoung
20e7a165-1aa2-4f5b-9958-e6a8113ddacb
Ryu, Kyoung-Seok
9e9ae702-2a2b-4e2c-82be-7e9282583014
Yeo, Won-Sik
c4020e9b-546b-4ace-9591-3f6f1e5cacd2
Bae, Taeok
f0044cf7-638f-4452-aded-73294b75242f
Kim, Dae Wook
e493a37e-4d3d-4909-947e-8c04c1590a07
Park, Ki Hun
ac34aaaf-0921-40a5-8ff8-29f43c90155a
Kim, Kyeong Kyu
a7757cb7-065e-4e76-a669-27d2108bef97
Lee, Seung Seo
ee34fa26-5fb6-48c8-80c2-1f13ec4ccceb
Mizar, Pushpak
631b688c-b7fb-41d7-8038-9fb48ef935c7
Arya, Rekha
4e1916f3-7fab-4f7f-b22a-ce84d73dd1da
Kim, Truc
64fff945-d3dc-4145-b714-d76a7024b786
Cha, Soyoung
20e7a165-1aa2-4f5b-9958-e6a8113ddacb
Ryu, Kyoung-Seok
9e9ae702-2a2b-4e2c-82be-7e9282583014
Yeo, Won-Sik
c4020e9b-546b-4ace-9591-3f6f1e5cacd2
Bae, Taeok
f0044cf7-638f-4452-aded-73294b75242f
Kim, Dae Wook
e493a37e-4d3d-4909-947e-8c04c1590a07
Park, Ki Hun
ac34aaaf-0921-40a5-8ff8-29f43c90155a
Kim, Kyeong Kyu
a7757cb7-065e-4e76-a669-27d2108bef97
Lee, Seung Seo
ee34fa26-5fb6-48c8-80c2-1f13ec4ccceb

Mizar, Pushpak, Arya, Rekha, Kim, Truc, Cha, Soyoung, Ryu, Kyoung-Seok, Yeo, Won-Sik, Bae, Taeok, Kim, Dae Wook, Park, Ki Hun, Kim, Kyeong Kyu and Lee, Seung Seo (2018) Total synthesis of xanthoangelol B and its various fragments: towards inhibition of virulence factor production of Staphylococcus aureus. Journal of Medicinal Chemistry, 61 (23), 10473–10487. (doi:10.1021/acs.jmedchem.8b01012).

Record type: Article

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 anti-virulence 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.

Text
ACS_ms_texts+Figs_Rev2-v2 - Accepted Manuscript
Download (1MB)
Text
acs.jmedchem.8b01012 - Version of Record
Available under License Creative Commons Attribution.
Download (4MB)

More information

Accepted/In Press date: 2 November 2018
e-pub ahead of print date: 2 November 2018
Published date: 13 December 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 426018
URI: http://eprints.soton.ac.uk/id/eprint/426018
ISSN: 0022-2623
PURE UUID: 3ae96bbe-dae9-4396-807e-0cbf0efdf3de
ORCID for Seung Seo Lee: ORCID iD orcid.org/0000-0002-8598-3303

Catalogue record

Date deposited: 09 Nov 2018 17:30
Last modified: 26 Nov 2021 05:13

Export record

Altmetrics

Contributors

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×