Rational Design of Potent Activators and Inhibitors of the Enterococcus faecalis Fsr Quorum Sensing Circuit

ACS Chemical Biology
Dominic N McBrayerYftah Tal-Gan

Abstract

The increasing rate of resistance development to conventional antibiotics by bacteria necessitates the identification of alternative treatment possibilities that can reduce the ability of bacteria to adapt. Enterococcus faecalis remains the leading cause of clinical enterococci infections and has exhibited quorum sensing (QS)-dependent pathogenicity. Here, we report the development of macrocyclic peptide-based activators and inhibitors of the E. faecalis Fsr QS circuitry. To this end, we developed, optimized, and compared three synthetic routes for lactone-containing macrocyclic peptide scaffolds. We then utilized previous and current structure-activity relationship (SAR) insights of the native QS signaling peptide to rationally design the most potent activators and inhibitors of the Fsr QS circuitry identified to date. The application of these peptides could provide a means to attenuate the pathogenicity of E. faecalis without introducing significant selective pressure on the bacteria to develop resistance.

References

Jun 11, 1998·Emerging Infectious Diseases·M M HuyckeM S Gilmore
Sep 6, 2001·Proceedings of the National Academy of Sciences of the United States of America·D A GarsinF M Ausubel
Apr 4, 2006·Analytical Chemistry·Dirk CheliusPavel V Bondarenko
Apr 23, 2009·Microbiology·Katie Fisher, Carol Phillips
Dec 8, 2011·Journal of Peptide Science : an Official Publication of the European Peptide Society·Christina Ann ChantellMahendra Menakuru
Mar 17, 2012·Nature Reviews. Microbiology·Cesar A Arias, Barbara E Murray
Nov 6, 2012·Cold Spring Harbor Perspectives in Medicine·Steven T Rutherford, Bonnie L Bassler
Feb 1, 2013·ACS Chemical Biology·Jiro NakayamaKenji Sonomoto
Oct 15, 2013·FEMS Microbiology Reviews·Laura C Cook, Michael J Federle
Jun 3, 2014·Marine Drugs·Kaihao Tang, Xiao-Hua Zhang
Jul 9, 2014·Annual Review of Microbiology·Daria Van Tyne, Michael S Gilmore
Aug 6, 2015·Infection and Drug Resistance·Tristan O'Driscoll, Christopher W Crank
Jan 21, 2016·Journal of Peptide Science : an Official Publication of the European Peptide Society·Raymond BehrendtJohn Offer
Aug 12, 2016·Nature Reviews. Microbiology·Kai Papenfort, Bonnie L Bassler
Feb 18, 2017·Trends in Pharmacological Sciences·Benjamin K Johnson, Robert B Abramovitch
Feb 25, 2017·Chemical Reviews·Megan GarlandMatthew Bogyo
May 19, 2018·Current Topics in Medicinal Chemistry·Ryan W MullYftah Tal-Gan
May 24, 2018·MBio·Rhea G AbisadoJosephine R Chandler

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Citations

Jan 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yifang YangYftah Tal-Gan
Sep 12, 2020·Organic & Biomolecular Chemistry·Dominic N McBrayerYftah Tal-Gan
Jun 22, 2019·ACS Medicinal Chemistry Letters·Bimal KoiralaYftah Tal-Gan
Nov 25, 2021·Science Translational Medicine·Pipat PiewngamMichael Otto

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