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Thiophenesulfonamides are specific inhibitors of quorum sensing in pathogenic Vibrios

Newman, Jane D. and Shah, Priyanka and Chopra, Jay and Shi, Eda and McFadden, Molly E. and Horness, Rachel E. and Brown, Laura C. and van Kessel, Julia C. (2021) Thiophenesulfonamides are specific inhibitors of quorum sensing in pathogenic Vibrios. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20210415-074717081

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Abstract

Vibrio bacteria are pathogens of fish, shellfish, coral, and humans due to contaminated seafood consumption. Vibrio virulence factors are controlled by the cell-to-cell communication called quorum sensing, thus this signaling system is a promising target for therapeutic design. We screened a compound library and identified nine compounds, including several 2-thiophenesulfonamides, that inhibit the master quorum sensing transcription factor LuxR in Vibrio campbellii but do not affect cell growth. We synthesized a panel of 50 thiophenesulfonamide compounds to examine the structure-activity relationship effects on quorum sensing in vivo. The most potent molecule identified, PTSP (3-phenyl-1-(thiophen-2-ylsulfonyl)-1H-pyrazole), specifically inhibits LuxR homologs in multiple strains of Vibrio vulnificus, Vibrio parahaemolyticus, and V. campbellii with sub-micromolar concentrations. PTSP efficacy is driven by amino acid conservation in the binding pocket, which is accurately predicted using in silico modeling of inhibitors. Our results underscore the potential for developing thiophenesulfonamides as specific quorum sensing-directed treatments for Vibrio infections.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2021.04.14.439868DOIDiscussion Paper
ORCID:
AuthorORCID
McFadden, Molly E.0000-0003-3174-6385
van Kessel, Julia C.0000-0002-1612-2403
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This version posted April 14, 2021. We thank Stanna Dorn and the Indiana University students in Organic Chemistry C344 laboratory classes for synthesis of molecules in the thiophenesulfonamide panel. We thank the Indiana University School of Medicine Chemical Genomics Core Facility for assistance with chemical screens and analyses. We thank Dr. Irene Newton for assistance with data analysis. Author Contributions: JVK and LCB designed the experiments, JVK, JDN, PS, JC, ES, MEM, and LCB performed experiments, JVK, JDN, RH, JC, ES, MEM, and LCB analyzed experimental results, and JVK, JDN, and LCB wrote the manuscript. The authors declare that they have no competing interests. This work was supported by National Institutes of Health grant R35GM124698 to JVK and with support from the Indiana Clinical and Translational Sciences Institute funded, in part by Award Number UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funders:
Funding AgencyGrant Number
NIHR35GM124698
Indiana Clinical and Translational Sciences InstituteUNSPECIFIED
NIHUL1TR002529
Record Number:CaltechAUTHORS:20210415-074717081
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20210415-074717081
Official Citation:Thiophenesulfonamides are specific inhibitors of quorum sensing in pathogenic Vibrios. Jane D Newman, Priyanka Shah, Jay Chopra, Eda Shi, Molly E McFadden, Rachel E Horness, Laura C Brown, Julia C van Kessel. bioRxiv 2021.04.14.439868; doi: https://doi.org/10.1101/2021.04.14.439868
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:108737
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:16 Apr 2021 20:04
Last Modified:19 Apr 2021 16:10

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