Small molecule probes of the receptor binding site in the Vibrio cholerae CAI-1 quorum sensing circuit

Megan E. Bolitho; Lark J. Perez; Matthew J. Koch; Wai Leung Ng; Bonnie Lynn Bassler; Martin F. Semmelhack

doi:10.1016/j.bmc.2011.09.021

Small molecule probes of the receptor binding site in the Vibrio cholerae CAI-1 quorum sensing circuit

Megan E. Bolitho, Lark J. Perez, Matthew J. Koch, Wai Leung Ng, Bonnie Lynn Bassler, Martin F. Semmelhack

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

23 Scopus citations

Abstract

Based on modification of separate structural features of the Vibrio cholerae quorum sensing signal, (S)-3-hydroxytridecan-4-one (CAI-1), three focused compound libraries have been synthesized and evaluated for biological activity. Modifications to the acyl tail and α-hydroxy ketone typically provided agonists with activities correlated to tail length and conservative changes to the hydroxy ketone. Among the molecules identified within this collection of agonists is Am-CAI-1 (B11), which is among the most potent agonists reported to date with an EC ₅₀ of 0.21 μM. Modifications to the ethyl side chain delivered molecules with both agonist and antagonist activity, including m-OH-Ph-CAI-1 (C13) which is the most potent antagonist reported to date with an IC ₅₀ of 36 μM. The molecules described in this manuscript are anticipated to serve as valuable tools in the study of quorum sensing in Vibrio cholerae and provide new leads in the development of an antivirulence therapy against this human pathogen.

Original language	English (US)
Pages (from-to)	6906-6918
Number of pages	13
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	22
DOIs	https://doi.org/10.1016/j.bmc.2011.09.021
State	Published - Nov 15 2011

All Science Journal Classification (ASJC) codes

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmaceutical Science
Organic Chemistry

Keywords

Agonist
Antagonist
Autoinducer
Quorum sensing
Structure-activity relationship
Vibrio cholerae

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10.1016/j.bmc.2011.09.021

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title = "Small molecule probes of the receptor binding site in the Vibrio cholerae CAI-1 quorum sensing circuit",

abstract = "Based on modification of separate structural features of the Vibrio cholerae quorum sensing signal, (S)-3-hydroxytridecan-4-one (CAI-1), three focused compound libraries have been synthesized and evaluated for biological activity. Modifications to the acyl tail and α-hydroxy ketone typically provided agonists with activities correlated to tail length and conservative changes to the hydroxy ketone. Among the molecules identified within this collection of agonists is Am-CAI-1 (B11), which is among the most potent agonists reported to date with an EC 50 of 0.21 μM. Modifications to the ethyl side chain delivered molecules with both agonist and antagonist activity, including m-OH-Ph-CAI-1 (C13) which is the most potent antagonist reported to date with an IC 50 of 36 μM. The molecules described in this manuscript are anticipated to serve as valuable tools in the study of quorum sensing in Vibrio cholerae and provide new leads in the development of an antivirulence therapy against this human pathogen.",

keywords = "Agonist, Antagonist, Autoinducer, Quorum sensing, Structure-activity relationship, Vibrio cholerae",

author = "Bolitho, {Megan E.} and Perez, {Lark J.} and Koch, {Matthew J.} and Ng, {Wai Leung} and Bassler, {Bonnie Lynn} and Semmelhack, {Martin F.}",

note = "Funding Information: The authors acknowledge Yongfeng Li and Karen Jeng for their contributions to the synthesis of analog compounds, to Douglas Higgins for early work on the biological evaluation of agonist analogs, and to Lotus Separations, LLC (Christina Kraml) for essential contributions to compound purification and chiral resolution. This work was supported by the Howard Hughes Medical Institute, National Institutes of Health (NIH) grant 5R01AI054442, National Science Foundation (NSF) grant MCB-0343821 to BLB, NIH postdoctoral fellowship GM082061 to W.L.N. and the Dr. Horst Witzel Prize from Cephalon, Inc. (MEB). ",

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doi = "10.1016/j.bmc.2011.09.021",

language = "English (US)",

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journal = "Bioorganic and Medicinal Chemistry",

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T1 - Small molecule probes of the receptor binding site in the Vibrio cholerae CAI-1 quorum sensing circuit

AU - Bolitho, Megan E.

AU - Perez, Lark J.

AU - Koch, Matthew J.

AU - Ng, Wai Leung

AU - Bassler, Bonnie Lynn

AU - Semmelhack, Martin F.

N1 - Funding Information: The authors acknowledge Yongfeng Li and Karen Jeng for their contributions to the synthesis of analog compounds, to Douglas Higgins for early work on the biological evaluation of agonist analogs, and to Lotus Separations, LLC (Christina Kraml) for essential contributions to compound purification and chiral resolution. This work was supported by the Howard Hughes Medical Institute, National Institutes of Health (NIH) grant 5R01AI054442, National Science Foundation (NSF) grant MCB-0343821 to BLB, NIH postdoctoral fellowship GM082061 to W.L.N. and the Dr. Horst Witzel Prize from Cephalon, Inc. (MEB).

PY - 2011/11/15

Y1 - 2011/11/15

N2 - Based on modification of separate structural features of the Vibrio cholerae quorum sensing signal, (S)-3-hydroxytridecan-4-one (CAI-1), three focused compound libraries have been synthesized and evaluated for biological activity. Modifications to the acyl tail and α-hydroxy ketone typically provided agonists with activities correlated to tail length and conservative changes to the hydroxy ketone. Among the molecules identified within this collection of agonists is Am-CAI-1 (B11), which is among the most potent agonists reported to date with an EC 50 of 0.21 μM. Modifications to the ethyl side chain delivered molecules with both agonist and antagonist activity, including m-OH-Ph-CAI-1 (C13) which is the most potent antagonist reported to date with an IC 50 of 36 μM. The molecules described in this manuscript are anticipated to serve as valuable tools in the study of quorum sensing in Vibrio cholerae and provide new leads in the development of an antivirulence therapy against this human pathogen.

AB - Based on modification of separate structural features of the Vibrio cholerae quorum sensing signal, (S)-3-hydroxytridecan-4-one (CAI-1), three focused compound libraries have been synthesized and evaluated for biological activity. Modifications to the acyl tail and α-hydroxy ketone typically provided agonists with activities correlated to tail length and conservative changes to the hydroxy ketone. Among the molecules identified within this collection of agonists is Am-CAI-1 (B11), which is among the most potent agonists reported to date with an EC 50 of 0.21 μM. Modifications to the ethyl side chain delivered molecules with both agonist and antagonist activity, including m-OH-Ph-CAI-1 (C13) which is the most potent antagonist reported to date with an IC 50 of 36 μM. The molecules described in this manuscript are anticipated to serve as valuable tools in the study of quorum sensing in Vibrio cholerae and provide new leads in the development of an antivirulence therapy against this human pathogen.

KW - Agonist

KW - Antagonist

KW - Autoinducer

KW - Quorum sensing

KW - Structure-activity relationship

KW - Vibrio cholerae

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ER -

Small molecule probes of the receptor binding site in the Vibrio cholerae CAI-1 quorum sensing circuit

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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