Small-molecule inhibitor of HlyU attenuates virulence of Vibrio species

Zee Won Lee; Byoung Sik Kim; Kyung Ku Jang; Ye Ji Bang; Suhyeon Kim; Nam Chul Ha; Young Hyun Jung; Hyun Jik Lee; Ho Jae Han; Jong Seo Kim; Jeesoo Kim; Pramod K. Sahu; Lak Shin Jeong; Myung Hee Kim; Sang Ho Choi

doi:10.1038/s41598-019-39554-y

Small-molecule inhibitor of HlyU attenuates virulence of Vibrio species

Zee Won Lee, Byoung Sik Kim, Kyung Ku Jang, Ye Ji Bang, Suhyeon Kim, Nam Chul Ha, Young Hyun Jung, Hyun Jik Lee, Ho Jae Han, Jong Seo Kim, Jeesoo Kim, Pramod K. Sahu, Lak Shin Jeong, Myung Hee Kim, Sang Ho Choi

Food Science and Biotechnology

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Increasing antibiotic resistance has led to the development of new strategies to combat bacterial infection. Anti-virulence strategies that impair virulence of bacterial pathogens are one of the novel approaches with less selective pressure for developing resistance than traditional strategies that impede viability. In this study, a small molecule CM14 [N-(4-oxo-4H-thieno[3,4-c]chromen-3-yl)-3-phenylprop-2-ynamide] that inhibits the activity of HlyU, a transcriptional regulator essential for the virulence of the fulminating human pathogen Vibrio vulnificus, has been identified. Without affecting bacterial growth or triggering the host cell death, CM14 reduces HlyU-dependent expression of virulence genes in V. vulnificus. In addition to the decreased hemolysis of human erythrocytes, CM14 impedes host cell rounding and lysis caused by V. vulnificus. Notably, CM14 significantly enhances survival of mice infected with V. vulnificus by alleviating hepatic and renal dysfunction and systemic inflammation. Biochemical, mass spectrometric, and mutational analyses revealed that CM14 inhibits HlyU from binding to target DNA by covalently modifying Cys30. Remarkably, CM14 decreases the expression of various virulence genes of other Vibrio species and thus attenuates their virulence phenotypes. Together, this molecule could be an anti-virulence agent against HlyU-harboring Vibrio species with a low selective pressure for the emergence of resistance.

Original language	English
Article number	4346
Journal	Scientific Reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-39554-y
State	Published - 1 Dec 2019

Bibliographical note

Funding Information:
We thank the Korea Chemical Bank for generously providing the small-molecule libraries. We also thank Professor Seok, Yeong-Jae, Seoul National University, for help in the V. cholerae experiments. This work was supported by National Research Foundation of Korea, funded by the Ministry of Science, ICT, and Future Planning (2017R1E1A1A01074639) and the Institute of Planning and Evaluation for Technology (IPET) of the Ministry of Agriculture, Food, and Rural Affairs (710012-03-2-SB110) to S.H.C, and by the Ewha Womans University Research Grant of 2018 to B.S.K.

Publisher Copyright:
© 2019, The Author(s).

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@article{8b4a779c6cfe4866989c7b896e9d37c2,

title = "Small-molecule inhibitor of HlyU attenuates virulence of Vibrio species",

abstract = "Increasing antibiotic resistance has led to the development of new strategies to combat bacterial infection. Anti-virulence strategies that impair virulence of bacterial pathogens are one of the novel approaches with less selective pressure for developing resistance than traditional strategies that impede viability. In this study, a small molecule CM14 [N-(4-oxo-4H-thieno[3,4-c]chromen-3-yl)-3-phenylprop-2-ynamide] that inhibits the activity of HlyU, a transcriptional regulator essential for the virulence of the fulminating human pathogen Vibrio vulnificus, has been identified. Without affecting bacterial growth or triggering the host cell death, CM14 reduces HlyU-dependent expression of virulence genes in V. vulnificus. In addition to the decreased hemolysis of human erythrocytes, CM14 impedes host cell rounding and lysis caused by V. vulnificus. Notably, CM14 significantly enhances survival of mice infected with V. vulnificus by alleviating hepatic and renal dysfunction and systemic inflammation. Biochemical, mass spectrometric, and mutational analyses revealed that CM14 inhibits HlyU from binding to target DNA by covalently modifying Cys30. Remarkably, CM14 decreases the expression of various virulence genes of other Vibrio species and thus attenuates their virulence phenotypes. Together, this molecule could be an anti-virulence agent against HlyU-harboring Vibrio species with a low selective pressure for the emergence of resistance.",

author = "Lee, {Zee Won} and Kim, {Byoung Sik} and Jang, {Kyung Ku} and Bang, {Ye Ji} and Suhyeon Kim and Ha, {Nam Chul} and Jung, {Young Hyun} and Lee, {Hyun Jik} and Han, {Ho Jae} and Kim, {Jong Seo} and Jeesoo Kim and Sahu, {Pramod K.} and Jeong, {Lak Shin} and Kim, {Myung Hee} and Choi, {Sang Ho}",

note = "Funding Information: We thank the Korea Chemical Bank for generously providing the small-molecule libraries. We also thank Professor Seok, Yeong-Jae, Seoul National University, for help in the V. cholerae experiments. This work was supported by National Research Foundation of Korea, funded by the Ministry of Science, ICT, and Future Planning (2017R1E1A1A01074639) and the Institute of Planning and Evaluation for Technology (IPET) of the Ministry of Agriculture, Food, and Rural Affairs (710012-03-2-SB110) to S.H.C, and by the Ewha Womans University Research Grant of 2018 to B.S.K. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41598-019-39554-y",

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AU - Lee, Zee Won

AU - Kim, Byoung Sik

AU - Jang, Kyung Ku

AU - Bang, Ye Ji

AU - Kim, Suhyeon

AU - Ha, Nam Chul

AU - Jung, Young Hyun

AU - Lee, Hyun Jik

AU - Han, Ho Jae

AU - Kim, Jong Seo

AU - Kim, Jeesoo

AU - Sahu, Pramod K.

AU - Jeong, Lak Shin

AU - Kim, Myung Hee

AU - Choi, Sang Ho

N1 - Funding Information: We thank the Korea Chemical Bank for generously providing the small-molecule libraries. We also thank Professor Seok, Yeong-Jae, Seoul National University, for help in the V. cholerae experiments. This work was supported by National Research Foundation of Korea, funded by the Ministry of Science, ICT, and Future Planning (2017R1E1A1A01074639) and the Institute of Planning and Evaluation for Technology (IPET) of the Ministry of Agriculture, Food, and Rural Affairs (710012-03-2-SB110) to S.H.C, and by the Ewha Womans University Research Grant of 2018 to B.S.K. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Increasing antibiotic resistance has led to the development of new strategies to combat bacterial infection. Anti-virulence strategies that impair virulence of bacterial pathogens are one of the novel approaches with less selective pressure for developing resistance than traditional strategies that impede viability. In this study, a small molecule CM14 [N-(4-oxo-4H-thieno[3,4-c]chromen-3-yl)-3-phenylprop-2-ynamide] that inhibits the activity of HlyU, a transcriptional regulator essential for the virulence of the fulminating human pathogen Vibrio vulnificus, has been identified. Without affecting bacterial growth or triggering the host cell death, CM14 reduces HlyU-dependent expression of virulence genes in V. vulnificus. In addition to the decreased hemolysis of human erythrocytes, CM14 impedes host cell rounding and lysis caused by V. vulnificus. Notably, CM14 significantly enhances survival of mice infected with V. vulnificus by alleviating hepatic and renal dysfunction and systemic inflammation. Biochemical, mass spectrometric, and mutational analyses revealed that CM14 inhibits HlyU from binding to target DNA by covalently modifying Cys30. Remarkably, CM14 decreases the expression of various virulence genes of other Vibrio species and thus attenuates their virulence phenotypes. Together, this molecule could be an anti-virulence agent against HlyU-harboring Vibrio species with a low selective pressure for the emergence of resistance.

AB - Increasing antibiotic resistance has led to the development of new strategies to combat bacterial infection. Anti-virulence strategies that impair virulence of bacterial pathogens are one of the novel approaches with less selective pressure for developing resistance than traditional strategies that impede viability. In this study, a small molecule CM14 [N-(4-oxo-4H-thieno[3,4-c]chromen-3-yl)-3-phenylprop-2-ynamide] that inhibits the activity of HlyU, a transcriptional regulator essential for the virulence of the fulminating human pathogen Vibrio vulnificus, has been identified. Without affecting bacterial growth or triggering the host cell death, CM14 reduces HlyU-dependent expression of virulence genes in V. vulnificus. In addition to the decreased hemolysis of human erythrocytes, CM14 impedes host cell rounding and lysis caused by V. vulnificus. Notably, CM14 significantly enhances survival of mice infected with V. vulnificus by alleviating hepatic and renal dysfunction and systemic inflammation. Biochemical, mass spectrometric, and mutational analyses revealed that CM14 inhibits HlyU from binding to target DNA by covalently modifying Cys30. Remarkably, CM14 decreases the expression of various virulence genes of other Vibrio species and thus attenuates their virulence phenotypes. Together, this molecule could be an anti-virulence agent against HlyU-harboring Vibrio species with a low selective pressure for the emergence of resistance.

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Small-molecule inhibitor of HlyU attenuates virulence of Vibrio species

Abstract

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