High-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway

Abstract The main components of the quorum-sensing system are expected to be favorable targets for drug development to combat various chronic infectious diseases. ComA of Streptococcus is an ATP-binding cassette transporter containing a peptidase domain (PEP), which is essential for the quorum-sensi...

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Autores principales:	Seiji Ishii, Kenji Fukui, Satoshi Yokoshima, Kazuo Kumagai, Youko Beniyama, Tetsuya Kodama, Tohru Fukuyama, Takayoshi Okabe, Tetsuo Nagano, Hirotatsu Kojima, Takato Yano
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/aca6c4a48bed412fbc0b345a06486644
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spelling	oai:doaj.org-article:aca6c4a48bed412fbc0b345a064866442021-12-02T11:52:36ZHigh-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway10.1038/s41598-017-03567-22045-2322https://doaj.org/article/aca6c4a48bed412fbc0b345a064866442017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03567-2https://doaj.org/toc/2045-2322Abstract The main components of the quorum-sensing system are expected to be favorable targets for drug development to combat various chronic infectious diseases. ComA of Streptococcus is an ATP-binding cassette transporter containing a peptidase domain (PEP), which is essential for the quorum-sensing signal production. Using high-throughput screening, we found a potent small molecule that suppressed the S. mutans quorum-sensing pathway through inhibition of PEP activity. The compound effectively attenuated the biofilm formation and competence development of S. mutans without inhibiting cell growth. The kinetic and structural studies with this molecule and a related compound unexpectedly revealed an allosteric site of PEP. This relatively hydrophobic site is thought to undergo large structural changes during the catalytic process. These compounds inhibit PEP activity by binding to and suppressing the structural changes of this site. These results showed that PEP is a good target for inhibitors of the Streptococcus quorum-sensing system.Seiji IshiiKenji FukuiSatoshi YokoshimaKazuo KumagaiYouko BeniyamaTetsuya KodamaTohru FukuyamaTakayoshi OkabeTetsuo NaganoHirotatsu KojimaTakato YanoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Seiji Ishii Kenji Fukui Satoshi Yokoshima Kazuo Kumagai Youko Beniyama Tetsuya Kodama Tohru Fukuyama Takayoshi Okabe Tetsuo Nagano Hirotatsu Kojima Takato Yano High-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway
description	Abstract The main components of the quorum-sensing system are expected to be favorable targets for drug development to combat various chronic infectious diseases. ComA of Streptococcus is an ATP-binding cassette transporter containing a peptidase domain (PEP), which is essential for the quorum-sensing signal production. Using high-throughput screening, we found a potent small molecule that suppressed the S. mutans quorum-sensing pathway through inhibition of PEP activity. The compound effectively attenuated the biofilm formation and competence development of S. mutans without inhibiting cell growth. The kinetic and structural studies with this molecule and a related compound unexpectedly revealed an allosteric site of PEP. This relatively hydrophobic site is thought to undergo large structural changes during the catalytic process. These compounds inhibit PEP activity by binding to and suppressing the structural changes of this site. These results showed that PEP is a good target for inhibitors of the Streptococcus quorum-sensing system.
format	article
author	Seiji Ishii Kenji Fukui Satoshi Yokoshima Kazuo Kumagai Youko Beniyama Tetsuya Kodama Tohru Fukuyama Takayoshi Okabe Tetsuo Nagano Hirotatsu Kojima Takato Yano
author_facet	Seiji Ishii Kenji Fukui Satoshi Yokoshima Kazuo Kumagai Youko Beniyama Tetsuya Kodama Tohru Fukuyama Takayoshi Okabe Tetsuo Nagano Hirotatsu Kojima Takato Yano
author_sort	Seiji Ishii
title	High-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway
title_short	High-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway
title_full	High-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway
title_fullStr	High-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway
title_full_unstemmed	High-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway
title_sort	high-throughput screening of small molecule inhibitors of the streptococcus quorum-sensing signal pathway
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/aca6c4a48bed412fbc0b345a06486644
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High-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway

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