Princeton Dockets # 08-2418, 12-2775 &
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.
cholera by reducing V. cholerae
virulence and biofilm formation
infections caused by other pathogenic bacteria (e.g., Vibrio sp. & Legionella sp.)
Novel mechanism of
DA, Pomianek ME, Kraml CM, Taylor RK, Semmelhack MF, Bassler BL. The major
Vibrio cholerae autoinducer and its role in virulence factor production.
2007 Dec 6;450(7171):883-6.
Y, Perez LJ, Ng WL, Semmelhack MF, Bassler BL. Mechanism
of Vibrio cholerae autoinducer-1 biosynthesis.
2011 Apr 15;6(4):356-65.
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
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
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.
protection is pending.