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ACS Infect Dis DOI:10.1021/acsinfecdis.6b00206

Identification of Highly Specific Diversity-Oriented Synthesis-Derived Inhibitors of Clostridium difficile.

Publication TypeJournal Article
Year of Publication2017
AuthorsDuvall, JR, Bedard, L, Naylor-Olsen, AM, Manson, AL, Bittker, JA, Sun, W, Fitzgerald, ME, He, Z, Lee, MD, Marie, J-C, Muncipinto, G, Rush, D, Xu, D, Xu, H, Zhang, M, Earl, AM, Palmer, MA, Foley, MA, Vacca, JP, Scherer, CA
JournalACS Infect Dis
Date Published2017 05 12
KeywordsAmino Acid Isomerases, Animals, Anti-Bacterial Agents, Bacterial Proteins, Clostridium difficile, Drug Design, Enterocolitis, Pseudomembranous, Female, Gene Expression, Gram-Negative Bacteria, Gram-Positive Bacteria, Heterocyclic Compounds, 2-Ring, Mice, Mice, Inbred C57BL, Microbial Sensitivity Tests, Phenylurea Compounds, Pyrroles, Quinolines, Species Specificity, Structure-Activity Relationship, Survival Analysis

In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C. difficile while having little to no activity against other intestinal anaerobes; preliminary evidence suggests that compounds from one of these scaffolds target the glutamate racemase. In vivo efficacy data suggest that both compound series may provide lead optimization candidates.


Alternate JournalACS Infect Dis
PubMed ID28215073
PubMed Central IDPMC5509442
Grant ListHHSN272200900018C / AI / NIAID NIH HHS / United States
U19 AI110818 / AI / NIAID NIH HHS / United States