Identification of Highly Specific Diversity-Oriented Synthesis-Derived Inhibitors of Clostridium difficile
Autor: | Wenye Sun, Zhenmin He, Adel M. Naylor-Olsen, Deming Xu, Joseph P. Vacca, Leanne Bedard, Ashlee M. Earl, Christina Scherer, Abigail L. Manson, Maurice D. Lee, Diane M Rush, Mark E. Fitzgerald, Mingliang Zhang, Huisheng Xu, Michelle Palmer, Joshua A. Bittker, Michael Foley, Jean-Charles Marie, Jeremy R. Duvall, Giovanni Muncipinto |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
030106 microbiology Gene Expression Virulence Microbial Sensitivity Tests Biology Gram-Positive Bacteria Heterocyclic Compounds 2-Ring Article Microbiology Mice Structure-Activity Relationship 03 medical and health sciences Bacterial Proteins Species Specificity In vivo Gram-Negative Bacteria Animals Glutamate racemase Pyrroles Enterocolitis Pseudomembranous Amino Acid Isomerases Clostridioides difficile Phenylurea Compounds Clostridium difficile C difficile Survival Analysis Disease control Anti-Bacterial Agents Mice Inbred C57BL 030104 developmental biology Infectious Diseases Drug Design Quinolines Female Identification (biology) DISEASE RELAPSE |
Zdroj: | ACS Infectious Diseases. 3:349-359 |
ISSN: | 2373-8227 |
Popis: | 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. |
Databáze: | OpenAIRE |
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