Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species

Ota, Natsuko; Nishida, Takashi; Standley, M. Daron; Sherif, Aalaa Alrahman; Iwano, Satoshi; Nugraha, Dendi Krisna; Ueno, Toshiya; Horiguchi, Yasuhiko

doi:https://doi.org/10.1111/1348-0421.13193

Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species

Ota, Natsuko; Nishida, Takashi; Standley, M. Daron et al.

Microbiology and Immunology, 2024

アクセス数:662件（2025-08-20 14:19 集計）

固定URL: https://hdl.handle.net/11094/100193

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タイトル	Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species
著者	著者名 Ota, Natsuko
	NRID 1000020845200 1000020845200 ORCID 0000-0003-4978-7716 0000-0003-4978-7716 researchmap permalink tnisida tnisida Scopus Author ID 53064412900 53064412900 著者名 Nishida, Takashi
	NRID 1000000448028 1000000448028 researchmap permalink 7000011861 7000011861 著者名 Standley, M. Daron
	著者名 Sherif, Aalaa Alrahman
	NRID 1000010734832 1000010734832 著者名 Iwano, Satoshi
	NRID 1000000963430 1000000963430 ORCID 0000-0002-6995-5695 0000-0002-6995-5695 researchmap permalink dendikrisna dendikrisna 著者名 Nugraha, Dendi Krisna
	著者名 Ueno, Toshiya
	NRID 1000000183939 1000000183939 ORCID 0000-0002-1592-5861 0000-0002-1592-5861 researchmap permalink read0014308 read0014308 Scopus Author ID 7102798909 7102798909 著者名 Horiguchi, Yasuhiko
キーワード等	Bordetella
	BvgAS
	lonidamine
	modulator
	phase conversion
内容	Ota N., Nishida T., Standley D.M., et al. Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species. Microbiology and Immunology , (2024); https://doi.org/10.1111/1348-0421.13193.
抄録	The Gram-negative bacteria Bordetella pertussis, B. parapertussis, and B. bronchiseptica cause respiratory diseases in various mammals. They share the BvgAS two-component system, which regulates the phenotypic conversion between the virulent Bvg+ and avirulent Bvg– phases. In the BvgAS system, the sensor kinase BvgS senses environmental cues and transduces a phosphorelay signal to the response regulator BvgA, which leads to the expression of Bvg+ phase-specific genes, including virulence factor genes. Bacteria grown at 37°C exhibit the Bvg+ phenotype. In contrast, at lower than 26°C or in the presence of modulators, such as MgSO4 and nicotinic acid, the BvgAS system is inactivated, leading bacteria to the avirulent Bvg– phase. Therefore, effective modulators are expected to provide a therapeutic measure for Bordetella infection; however, no such modulators are currently available, and the mechanism by which modulators inactivate the BvgAS system is poorly understood. In the present study, we identified lonidamine as a novel modulator after screening an FDA-approved drug library using bacterial reporter systems with the Bvg+-specific and Bvg–-specific promoters. Lonidamine directly bound to the VFT2 domain of BvgS and inactivated the BvgAS system at concentrations as low as 50 nM, which was at least 2000- to 20,000-fold lower than the effective concentrations of known modulators. Lonidamine significantly reduced the adherence of B. pertussis to cultured cells but unexpectedly exacerbated bacterial colonization of the mouse nasal septum. These results provide insights into the structural requirements for BvgAS modulators and the role of Bvg phenotypes in the establishment of infection.
出版者	John Wiley and Sons Inc
収録物名	Microbiology and Immunology
刊行年月	2024-12-15
言語	英語
ハンドルURL	https://hdl.handle.net/11094/100193
PISSN	03855600
eISSN	13480421
関連情報 (isIdenticalTo)	DOI (出版社版) https://doi.org/10.1111/1348-0421.13193
アクセス権	open access
権利情報	This article is licensed under a Creative Commons Attribution 4.0 International License.
出版タイプ	Version of Record
カテゴリ	学術雑誌論文 Journal Article

資源タイプ	学術雑誌論文
ローカル資源タイプ	学術雑誌論文
DCTERMS.bibliographicCitation	Microbiology and Immunology. 2024
DC.title	Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species
DC.creator	Ota, Natsuko
	Nishida, Takashi
	Standley, M. Daron
	Sherif, Aalaa Alrahman
	Iwano, Satoshi
	Nugraha, Dendi Krisna
	Ueno, Toshiya
	Horiguchi, Yasuhiko
DC.publisher	John Wiley and Sons Inc
DC.language' scheme='DCTERMS.RFC1766	英語
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-12-15
DC.identifier	https://doi.org/10.1111/1348-0421.13193
DC.subject	Bordetella
	BvgAS
	lonidamine
	modulator
	phase conversion
DC.description	Ota N., Nishida T., Standley D.M., et al. Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species. Microbiology and Immunology , (2024); https://doi.org/10.1111/1348-0421.13193.
DCTERMS.abstract	The Gram-negative bacteria Bordetella pertussis, B. parapertussis, and B. bronchiseptica cause respiratory diseases in various mammals. They share the BvgAS two-component system, which regulates the phenotypic conversion between the virulent Bvg+ and avirulent Bvg– phases. In the BvgAS system, the sensor kinase BvgS senses environmental cues and transduces a phosphorelay signal to the response regulator BvgA, which leads to the expression of Bvg+ phase-specific genes, including virulence factor genes. Bacteria grown at 37°C exhibit the Bvg+ phenotype. In contrast, at lower than 26°C or in the presence of modulators, such as MgSO4 and nicotinic acid, the BvgAS system is inactivated, leading bacteria to the avirulent Bvg– phase. Therefore, effective modulators are expected to provide a therapeutic measure for Bordetella infection; however, no such modulators are currently available, and the mechanism by which modulators inactivate the BvgAS system is poorly understood. In the present study, we identified lonidamine as a novel modulator after screening an FDA-approved drug library using bacterial reporter systems with the Bvg+-specific and Bvg–-specific promoters. Lonidamine directly bound to the VFT2 domain of BvgS and inactivated the BvgAS system at concentrations as low as 50 nM, which was at least 2000- to 20,000-fold lower than the effective concentrations of known modulators. Lonidamine significantly reduced the adherence of B. pertussis to cultured cells but unexpectedly exacerbated bacterial colonization of the mouse nasal septum. These results provide insights into the structural requirements for BvgAS modulators and the role of Bvg phenotypes in the establishment of infection.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	100193
citation_title	Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species
citation_author	Ota, Natsuko
	Nishida, Takashi
	Standley, M. Daron
	Sherif, Aalaa Alrahman
	Iwano, Satoshi
	Nugraha, Dendi Krisna
	Ueno, Toshiya
	Horiguchi, Yasuhiko
citation_publisher	John Wiley and Sons Inc
citation_language	英語
citation_date	2024-12-15
citation_journal_title	Microbiology and Immunology
citation_doi	https://doi.org/10.1111/1348-0421.13193
citation_public_url	https://hdl.handle.net/11094/100193

Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species

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