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

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

Microbiology and Immunology, 2024

Number of Access:662（2025-08-20 06:44 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100193

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Title
Lonidamine, a Novel Modulator for the BvgAS System of Bordetella Species
Creator
CreatorName
Ota, Natsuko
NRID
1000020845200 1000020845200
ORCID
0000-0003-4978-7716 0000-0003-4978-7716
researchmap permalink
tnisida tnisida
Scopus Author ID
53064412900 53064412900
CreatorName
Nishida, Takashi
NRID
1000000448028 1000000448028
researchmap permalink
7000011861 7000011861
CreatorName
Standley, M. Daron
CreatorName
Sherif, Aalaa Alrahman
NRID
1000010734832 1000010734832
CreatorName
Iwano, Satoshi
NRID
1000000963430 1000000963430
ORCID
0000-0002-6995-5695 0000-0002-6995-5695
researchmap permalink
dendikrisna dendikrisna
CreatorName
Nugraha, Dendi Krisna
CreatorName
Ueno, Toshiya
NRID
1000000183939 1000000183939
ORCID
0000-0002-1592-5861 0000-0002-1592-5861
researchmap permalink
read0014308 read0014308
Scopus Author ID
7102798909 7102798909
CreatorName
Horiguchi, Yasuhiko
Subject
Bordetella
BvgAS
lonidamine
modulator
phase conversion
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.
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.
Publisher
John Wiley and Sons Inc
Source Title
Microbiology and Immunology
Date of Issued
2024-12-15
Language
English
Handle URL
https://hdl.handle.net/11094/100193
PISSN
03855600
eISSN
13480421
Relation.isIdenticalTo
DOI (Publisher Version)
https://doi.org/10.1111/1348-0421.13193
Access Rights
open access
CopyRight
This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version
Version of Record
Category
学術雑誌論文 Journal Article