Open AccessUltrapotent Inhibitor of Clostridioides difficile Growth, Which Suppresses Recurrence In Vivo
Author(s) -
George A Naclerio,
Nader S. Abutaleb,
Daoyi Li,
Mohamed N. Seleem,
Herman O. Sintim
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01198
Subject(s) - clostridioides , in vivo , antibiotics , chemistry , vancomycin , microbiology and biotechnology , potency , bacteria , pharmacology , in vitro , medicine , biology , biochemistry , genetics , staphylococcus aureus
Clostridioides difficile is the leading cause of healthcare-associated infection in the U.S. and considered an urgent threat by the Centers for Disease Control and Prevention (CDC). Only two antibiotics, vancomycin and fidaxomicin, are FDA-approved for the treatment of C. difficile infection (CDI), but these therapies still suffer from high treatment failure and recurrence. Therefore, new chemical entities to treat CDI are needed. Trifluoromethylthio-containing N -(1,3,4-oxadiazol-2-yl)benzamides displayed very potent activities [sub-μg/mL minimum inhibitory concentration (MIC) values] against Gram-positive bacteria. Here, we report remarkable antibacterial activity enhancement via halogen substitutions, which afforded new anti- C. difficile agents with ultrapotent activities [MICs as low as 0.003 μg/mL (0.007 μM)] that surpassed the activity of vancomycin against C. difficile clinical isolates. The most promising compound in the series, HSGN-218 , is nontoxic to mammalian colon cells and is gut-restrictive. In addition, HSGN-218 protected mice from CDI recurrence. Not only does this work provide a potential clinical lead for the development of C. difficile therapeutics but also highlights dramatic drug potency enhancement via halogen substitution.