Novel Compounds for Treating Cholera and Other Infections: Potent Agonists of the Quorum Sensing Circuit

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Princeton Dockets # 08-2418, 12-2775 & 12-2776

Cholera, an infection caused by the bacterium Vibrio cholerae, is a life-threatening disease.  It is estimated that cholera affects 3-5 million people worldwide, and causes 100,000-130,000 deaths a year as of 2010.  Antibiotics such as doxycycline and cotrimoxazole have been used to shorten the course of the disease and reduce the severity of the symptoms.  However, with antibiotic resistance on the rise, novel antimicrobials with different mechanisms of action are in urgent need.

Researchers at Princeton University have discovered a number of novel compounds that act as potent inhibitors of V. cholerae virulence and biofilm formation, and they function by an entirely novel mechanism.  These molecules modulate quorum sensing. Quorum sensing is a process of bacterial cell-cell communication that involves the production, release, and detection of secreted signaling molecules called autoinducers.  Quorum sensing allows populations of bacteria to collectively regulate gene expression and thereby act like multicellular organisms by carrying out tasks in synchrony.  Several clinically-relevant bacteria include V. cholerae use the CqsA/CqsS quorum sensing system to control the production of virulence factors and biofilm formation.  Notably, V. cholerae requires repression of this quorum sensing system to establish an infection in its host.  Therefore, novel strategies that activate quorum sensing in V. cholerae (and other bacteria that rely on CqsA/CqsS) thereby inhibiting virulence and diminishing infection, could have a range of clinical implications.

                  Using rational molecule design coupled with extensive SAR investigatoins, researchers have conceived of and synthesized a set of structurally distinct and potent small molecule agonists of V. cholerae quorum sensing.  Lead compounds have been identified that possess potent agonistic activity, and are currently being examined in animal models for inhibition of bacterial pathogenicity.  A class of quorum sensing antagonists have also been designed and synthesized for research purposes.  Further, rapid and high-yield synthesis pathways have been developed, greatly facilitating future research and development.



·         To treat/prevent cholera by reducing V. cholerae virulence and biofilm formation

·         To treat/prevent infections caused by other pathogenic bacteria (e.g., Vibrio sp. & Legionella sp.)



·         Novel mechanism of action

·         Rapid and high-yield synthesis



Higgins DA, Pomianek ME, Kraml CM, Taylor RK, Semmelhack MF, Bassler BL. The major Vibrio cholerae autoinducer and its role in virulence factor production. Nature. 2007 Dec 6;450(7171):883-6.

Wei Y, Perez LJ, Ng WL, Semmelhack MF, Bassler BL. Mechanism of Vibrio cholerae autoinducer-1 biosynthesis. ACS Chem Biol. 2011 Apr 15;6(4):356-65.

Bolitho ME, Perez LJ, Koch MJ, Ng WL, Bassler BL, Semmelhack MF. Small molecule probes of the receptor binding site in the Vibrio cholerae CAI-1 quorum sensing circuit. Bioorg Med Chem. 2011 Nov 15;19(22):6906-18.

The Inventors

Bonnie Bassler is the Squibb Professor in the Department of Molecular Biology, a Howard Hughes Medical Institute Investigator, and the Director of Council on Science and Technology at Princeton University.  Professor Bassler studies the molecular mechanisms that bacteria use to communicate with one another, and her aims include combating deadly bacterial diseases and understanding cell signaling in higher organisms.  She is the immediate past President of American Society for Microbiology (2010-2011) and she is currently the Chair of the Board of Governors of the American Academy of Microbiology (2011-2013). She is a member of the President of the United States¿ National Science Board (2011-2017). Among the numerous honors she has received are the Richard Lounsbery Award (2011), Wiley Prize in Biomedical Sciences (2009), election to the American Academy of Arts and Sciences (2007), election to National Academy of Sciences (2006), Eli Lily Award (2005), and a MacArthur Foundation Fellowship (2002).

Martin Semmelhack is Professor in the Department of Chemistry at Princeton University.  His research is focused on Organic Synthesis and Organometallic Chemistry: new synthesis methodology involving organo-transition metal intermediates and applications in complex synthesis; design, synthesis, and evaluation of functional analogs of the enediyne natural toxins; the chemical biology of quorum sensing in bacteria. 

Intellectual Property status

Patent protection is pending.

Patent Information:
For Information, Contact:
Laurie Tzodikov
Licensing Associates
Princeton University
Martin Semmelhack
Bonnie Bassler
Lark Perez
Megan Bolitho
Matthew Koch
Wai-Leung Ng
small molecule