title: Identification of Highly Specific Diversity-Oriented Synthesis-Derived Inhibitors of Clostridium difficile.
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.
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.affiliation: WuXi AppTec Early Risk Sharing Group , 1690 Sumneytown Pike, Suite 150, Lansdale, Pennsylvania 19446, United States.
authors.forename: Leanne
authors.initials: L
authors.lastname: Bedard
authors.affiliation: WuXi AppTec Early Risk Sharing Group , 1690 Sumneytown Pike, Suite 150, Lansdale, Pennsylvania 19446, United States.
authors.forename: Adel M
authors.initials: AM
authors.lastname: Naylor-Olsen
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Manson
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bittker
authors.affiliation: WuXi AppTec , 168 Nanhai Road, TEDA, Tianjin 300457, China.
authors.forename: Wenye
authors.initials: W
authors.lastname: Sun
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fitzgerald
authors.affiliation: WuXi AppTec , 168 Nanhai Road, TEDA, Tianjin 300457, China.
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: He
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Maurice D
authors.initials: MD
authors.lastname: Lee
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Marie
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Muncipinto
authors.affiliation: WuXi AppTec Early Risk Sharing Group , 1690 Sumneytown Pike, Suite 150, Lansdale, Pennsylvania 19446, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Rush
authors.affiliation: WuXi AppTec , 168 Nanhai Road, TEDA, Tianjin 300457, China.
authors.forename: Deming
authors.initials: D
authors.lastname: Xu
authors.affiliation: WuXi AppTec , 168 Nanhai Road, TEDA, Tianjin 300457, China.
authors.forename: Huisheng
authors.initials: H
authors.lastname: Xu
authors.affiliation: WuXi AppTec , 168 Nanhai Road, TEDA, Tianjin 300457, China.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Ashlee M
authors.initials: AM
authors.lastname: Earl
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Palmer
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Foley
authors.affiliation: WuXi AppTec Early Risk Sharing Group , 1690 Sumneytown Pike, Suite 150, Lansdale, Pennsylvania 19446, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.affiliation: Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Christina A
authors.identifier: 0000-0002-1659-2827
authors.initials: CA
authors.lastname: Scherer
mesh_terms: D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016360:Clostridioides difficile / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D015195:Drug Design; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000254:growth & development; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; C000625210:BRD0761; C000625209:BRD3098; D001426:Bacterial Proteins; D006574:Heterocyclic Compounds, 2-Ring; D010671:Phenylurea Compounds; D011758:Pyrroles; D011804:Quinolines; D000591:Amino Acid Isomerases; C062292:glutamate racemase
keywords: C. difficile; CDAD; diversity-oriented synthesis; glutamate racemase