High-throughput identification of chemical inhibitors of E. coli Group 2 capsule biogenesis as anti-virulence agents.
Abstract
Rising antibiotic resistance among Escherichia coli, the leading cause of urinary
tract infections (UTIs), has placed a new focus on molecular pathogenesis studies,
aiming to identify new therapeutic targets. Anti-virulence agents are attractive as
chemotherapeutics to attenuate an organism during disease but not necessarily during
benign commensalism, thus decreasing the stress on beneficial microbial communities
and lessening the emergence of resistance. We and others have demonstrated that the
K antigen capsule of E. coli is a preeminent virulence determinant during UTI and
more invasive diseases. Components of assembly and export are highly conserved among
the major K antigen capsular types associated with UTI-causing E. coli and are distinct
from the capsule biogenesis machinery of many commensal E. coli, making these attractive
therapeutic targets. We conducted a screen for anti-capsular small molecules and identified
an agent designated "C7" that blocks the production of K1 and K5 capsules, unrelated
polysaccharide types among the Group 2-3 capsules. Herein lies proof-of-concept that
this screen may be implemented with larger chemical libraries to identify second-generation
small-molecule inhibitors of capsule biogenesis. These inhibitors will lead to a better
understanding of capsule biogenesis and may represent a new class of therapeutics.
Type
Journal articleSubject
Anti-Bacterial AgentsAntigens, Bacterial
Antigens, Surface
Bacterial Capsules
Escherichia coli
Humans
Virulence
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https://hdl.handle.net/10161/4554Published Version (Please cite this version)
10.1371/journal.pone.0011642Publication Info
Goller, Carlos C; & Seed, Patrick C (2010). High-throughput identification of chemical inhibitors of E. coli Group 2 capsule biogenesis
as anti-virulence agents. PLoS One, 5(7). pp. e11642. 10.1371/journal.pone.0011642. Retrieved from https://hdl.handle.net/10161/4554.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Patrick Casey Seed
Associate Professor of Pediatrics
We are studying human microbial ecology and the molecular basis for different bacterial
infections that are of relevance to both children and adults. Summaries of the research
areas are described below: 1. THE MOLECULAR BASIS FOR VIRULENCE OF UROPATHOGENIC
ESCHERICHIA COLI AND URINARY TRACT INFECTIONS. Uropathogenic Escherichia coli (UPEC)
is the leading cause of community-acquired urinary tract infections (UTIs). Over
100 million UTIs occur annually throughout the world inclu

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