Amino acid divergence in the ligand-binding pocket of Vibrio LuxR/HapR proteins determines the efficacy of thiophenesulfonamide inhibitors.

Molecular Microbiology
Jane D NewmanJulia C van Kessel

Abstract

The quorum-sensing signaling systems in Vibrio bacteria converge to control levels of the master transcription factors LuxR/HapR, a family of highly conserved proteins that regulate gene expression for bacterial behaviors. A compound library screen identified 2-thiophenesulfonamide compounds that specifically inhibit Vibrio campbellii LuxR but do not affect cell growth. We synthesized a panel of 50 thiophenesulfonamide compounds to examine the structure-activity relationship effects on Vibrio quorum sensing. The most potent molecule identified, PTSP (3-phenyl-1-(thiophen-2-ylsulfonyl)-1H-pyrazole), inhibits quorum sensing in multiple strains of V. vulnificus, V. parahaemolyticus, and V. campbellii at nanomolar concentrations. However, thiophenesulfonamide inhibition efficacy varies significantly among Vibrio species: PTSP is most inhibitory against V. vulnificus SmcR, but V. cholerae HapR is completely resistant to all thiophenesulfonamides tested. Reverse genetics experiments show that PTSP efficacy is dictated by amino acid sequence in the putative ligand-binding pocket: F75Y and C170F SmcR substitutions are each sufficient to eliminate PTSP inhibition. Further, in silico modeling distinguished the most potent thiophenesulfon...Continue Reading

References

Apr 1, 1996·Molecular Microbiology·J ChatterjeeE A Meighen
Sep 26, 2003·Molecular Microbiology·Brian K Hammer, Bonnie L Bassler
Oct 11, 2003·Developmental Cell·Jun Zhu, John J Mekalanos
Jun 10, 2005·Microbiology and Molecular Biology Reviews : MMBR·Juan L RamosRaquel Tobes
Nov 3, 2005·Molecular Microbiology·Derrick H LenzBonnie L Bassler
May 29, 2007·Journal of Bacteriology·Rukman S De SilvaF Jon Kull
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Aug 19, 2009·Annual Review of Genetics·Wai-Leung Ng, Bonnie L Bassler
Oct 20, 2009·Applied and Environmental Microbiology·Hiroaki Hasegawa, Claudia C Häse
Feb 18, 2011·Genes & Development·Steven T RutherfordBonnie L Bassler
Apr 7, 2011·Biocontrol Science·Sumio Shinoda, Shin-Ichi Miyoshi
May 18, 2012·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Anna NewtonBarbara E Mahon
May 23, 2012·ACS Chemical Biology·Bernadette M HenaresElizabeth M Boon
Nov 6, 2012·Cold Spring Harbor Perspectives in Medicine·Steven T Rutherford, Bonnie L Bassler
Jul 19, 2013·Future Medicinal Chemistry·Dalia I HammoudehRichard E Lee
Aug 24, 2013·International Journal of Molecular Sciences·Bernadette M HenaresElizabeth M Boon
Oct 18, 2013·The New England Journal of Medicine·Jaime Martinez-UrtazaAngelo DePaola
Oct 24, 2013·Foodborne Pathogens and Disease·Ignace ColyJaime Martinez-Urtaza
Nov 8, 2015·Current Genetics·Sarah A JungWai-Leung Ng
Aug 10, 2016·Proceedings of the National Academy of Sciences of the United States of America·Luigi VezzulliCarla Pruzzo
Mar 21, 2017·Nature Chemical Biology·Kai PapenfortBonnie L Bassler
Mar 23, 2018·Frontiers in Pharmacology·Benjamin RémyDavid Daudé
Aug 1, 2018·ACS Chemical Biology·Sajjad HossainElizabeth M Boon
May 14, 2019·BioMed Research International·Qian JiangKang Yao

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