Structure-Based Design and Biological Evaluation of Triphenyl Scaffold-Based Hybrid Compounds as Hydrolytically Stable Modulators of a LuxR-Type Quorum Sensing Receptor

ACS Infectious Diseases
Matthew C O'Reilly, Helen E Blackwell

Abstract

Many common bacterial pathogens utilize quorum sensing to coordinate group behaviors and initiate virulence at high cell densities. The use of small molecules to block quorum sensing provides a means of abrogating pathogenic phenotypes, but many known quorum sensing modulators have limitations, including hydrolytic instability and displaying non-monotonic dose curves (indicative of additional targets and/or modes of action). To address these issues, we undertook a structure-based scaffold-hopping approach to develop new chemical modulators of the LasR quorum sensing receptor in Pseudomonas aeruginosa. We combined components from a triphenyl derivative known to strongly agonize LasR with chemical moieties known for LasR antagonism and generated potent LasR antagonists that are hydrolytically stable across a range of pH values. Additionally, many of these antagonists do not exhibit non-monotonic dose effects, delivering probes that inhibit LasR across a wider range of assay conditions relative to known lactone-based ligands.

References

Sep 5, 2002·Nature Reviews. Molecular Cell Biology·Clay Fuqua, E Peter Greenberg
Mar 20, 2003·Journal of Bacteriology·Victoria E WagnerBarbara H Iglewski
Jul 26, 2003·The EMBO Journal·Morten HentzerMichael Givskov
Nov 10, 2004·Organic & Biomolecular Chemistry·Freija G GlansdorpDavid R Spring
Feb 8, 2005·American Journal of Respiratory and Critical Care Medicine·Ruxana T SadikotAlice S Prince
Sep 15, 2005·Journal of the American Chemical Society·Grant D GeskeHelen E Blackwell
Nov 2, 2005·FEMS Microbiology Letters·Egon A OzerJoseph Zabner
Feb 25, 2006·Science·Andrew Camilli, Bonnie L Bassler
Mar 2, 2006·Journal of the American Chemical Society·Gunnar F KaufmannKim D Janda
Sep 13, 2006·Antimicrobial Agents and Chemotherapy·Ute MühE Peter Greenberg
Nov 1, 2006·Proceedings of the National Academy of Sciences of the United States of America·Ute MühE Peter Greenberg
Feb 6, 2007·Nature Reviews. Microbiology·Gerard D Wright
Aug 22, 2007·Nature Chemical Biology·Anne E ClatworthyDeborah T Hung
Dec 15, 2007·Nature Reviews. Microbiology·Lynette CegelskiScott J Hultgren
Jan 4, 2008·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Brad SpellbergUNKNOWN Infectious Diseases Society of America
Sep 2, 2008·Bioorganic & Medicinal Chemistry Letters·Grant D GeskeHelen E Blackwell
Jul 10, 2009·Journal of the American Chemical Society·Neri AmaraMichael M Meijler
Jan 6, 2010·EMBO Molecular Medicine·Jacqueline Njoroge, Vanessa Sperandio
Aug 3, 2010·The Journal of Organic Chemistry·Margrith E Mattmann, Helen E Blackwell
Nov 23, 2010·Chemical Reviews·Neri AmaraMichael M Meijler
Feb 26, 2011·Journal of the American Chemical Society·Joseph S ZakhariKim D Janda
Mar 19, 2011·Journal of Medicinal Chemistry·Nicholas A Meanwell
Apr 26, 2011·Journal of the American Chemical Society·Josep RayoMichael M Meijler
Jul 30, 2011·Bioorganic & Medicinal Chemistry·Christine E McInnis, Helen E Blackwell
Jul 30, 2011·Bioorganic & Medicinal Chemistry·Christine E McInnis, Helen E Blackwell
Apr 14, 2012·Organic & Biomolecular Chemistry·James T HodgkinsonDavid R Spring
Jul 10, 2012·Trends in Microbiology·Warren R J D GallowayDavid R Spring
Sep 6, 2012·Organic & Biomolecular Chemistry·Thanit PraneenararatHelen E Blackwell
Nov 6, 2012·Cold Spring Harbor Perspectives in Medicine·Steven T Rutherford, Bonnie L Bassler
Apr 20, 2013·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Helen W BoucherUNKNOWN Infectious Diseases Society of America
Oct 22, 2013·Proceedings of the National Academy of Sciences of the United States of America·Colleen T O'LoughlinBonnie L Bassler
Jan 31, 2014·Chembiochem : a European Journal of Chemical Biology·Joseph D MooreHelen E Blackwell
Feb 24, 2015·ACS Medicinal Chemistry Letters·Kevin T O'BrienLark J Perez

❮ Previous
Next ❯

Citations

Jan 12, 2017·ACS Infectious Diseases·Emma G SunebyTanya L Schneider
Dec 23, 2016·Chembiochem : a European Journal of Chemical Biology·Joseph K VasquezHelen E Blackwell
Dec 1, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Sizhe LiLaurent Soulère
Apr 25, 2019·International Journal of Molecular Sciences·Viola Camilla ScoffoneSilvia Buroni
Jun 9, 2016·FEMS Microbiology Reviews·Michael A Welsh, Helen E Blackwell
Aug 23, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Suhaib SadiqAbdul Rauf Siddiqi

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.