High-throughput identification of chemical inhibitors of E. coli Group 2 capsule biogenesis as anti-virulence agents.

PloS One
Carlos C Goller, Patrick C Seed

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...Continue Reading

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Mar 21, 2012·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Jonas MarschallUNKNOWN CDC Prevention Epicenters Program
Apr 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Lisa M WillisChris Whitfield
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Mar 22, 2016·Microbiology Spectrum·Steven Clegg, Caitlin N Murphy
May 27, 2016·Microbiology Spectrum·Sarah E Maddocks

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Methods Mentioned

BETA
dot blot

Software Mentioned

BLAST
Graph Pad Prism
Basic Local Alignment Search Tool ( BLAST
Image J
Graph Pad

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