Abstract
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.
Keywords:
C. difficile; CDAD; diversity-oriented synthesis; glutamate racemase.
MeSH terms
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Amino Acid Isomerases / antagonists & inhibitors*
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Amino Acid Isomerases / genetics
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Amino Acid Isomerases / metabolism
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Animals
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / pharmacology*
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Clostridioides difficile / drug effects*
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Clostridioides difficile / enzymology
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Clostridioides difficile / genetics
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Clostridioides difficile / growth & development
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Drug Design
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Enterocolitis, Pseudomembranous / drug therapy*
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Enterocolitis, Pseudomembranous / microbiology
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Enterocolitis, Pseudomembranous / mortality
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Enterocolitis, Pseudomembranous / pathology
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Female
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Gene Expression
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Gram-Negative Bacteria / drug effects
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Gram-Negative Bacteria / growth & development
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Gram-Positive Bacteria / drug effects
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Gram-Positive Bacteria / growth & development
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Heterocyclic Compounds, 2-Ring / chemical synthesis
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Heterocyclic Compounds, 2-Ring / pharmacology*
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Mice
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Mice, Inbred C57BL
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Microbial Sensitivity Tests
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Phenylurea Compounds / chemical synthesis
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Phenylurea Compounds / pharmacology*
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Pyrroles / chemical synthesis
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Pyrroles / pharmacology*
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Quinolines / chemical synthesis
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Quinolines / pharmacology*
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Species Specificity
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Structure-Activity Relationship
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Survival Analysis
Substances
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Anti-Bacterial Agents
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BRD0761
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BRD3098
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Bacterial Proteins
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Heterocyclic Compounds, 2-Ring
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Phenylurea Compounds
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Pyrroles
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Quinolines
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Amino Acid Isomerases
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glutamate racemase