September 24, 2020
Ultrapotent compound may help treat C. diff, reduce recurrence
WEST LAFAYETTE, Ind. – Clostridioides difficile, or C. diff, is the leading cause of health care-associated infection in the U.S.
Only two antibiotics, vancomycin and fidaxomicin, are FDA-approved for the treatment of C. diff, but even these therapies suffer from high treatment failure and recurrence.
Now, Purdue University innovators have advanced novel compounds that they developed to help treat patients with C. diff, one of only four bacteria considered an urgent threat by the Centers for Disease Control and Prevention. Their work is published in the Journal of Medicinal Chemistry.
“Our compounds have several advantages, including ultrapotent activities with minimum inhibitory concentration values as low as 0.003 μg/mL,” said Herman O. Sintim, the Drug Discovery Professor of Chemistry in Purdue’s Department of Chemistry. “Our compounds also do not kill good bacteria at concentrations that kill C. diff and performed significantly better than current antibiotics in preventing recurrence. These are significant advantages for patients dealing with this difficult bacterial infection.”
The most promising of the Purdue compounds, containing trifluoromethylthio functional group, is HSGN-218. Sintim said it has been shown to be one of the most potent compounds ever produced for use against C. diff.
“This is part of our work to create new solutions to treat diseases and infections that are resistant to current treatment options,” said Sintim, who is a member of the Purdue University Center for Cancer Research and the Purdue Institute for Drug Discovery. “This work provides a potential clinical lead for the development of C. diff therapeutics and also highlights dramatic drug potency enhancement via halogen substitution.”
The researchers patented their compounds through the Purdue Research Foundation Office of Technology Commercialization, which is looking for partners to advance the technology. For more information, contact Joseph Kasper at OTC at email@example.com and mention track code 2019-SINT-68535.
George Naclerio, a researcher on Sintim’s team, has been awarded a National Institutes of Health T32 training grant to help facilitate the development of this technology.
About Purdue Research Foundation Office of Technology Commercialization
The Purdue Research Foundation Office of Technology Commercialization operates one of the most comprehensive technology transfer programs among leading research universities in the U.S. Services provided by this office support the economic development initiatives of Purdue University and benefit the university's academic activities through commercializing, licensing and protecting Purdue intellectual property. The office recently moved into the Convergence Center for Innovation and Collaboration in Discovery Park District, adjacent to the Purdue campus. In fiscal year 2020, the office reported 148 deals finalized with 225 technologies signed, 408 disclosures received and 180 issued U.S. patents. The office is managed by the Purdue Research Foundation, which received the 2019 Innovation and Economic Prosperity Universities Award for Place from the Association of Public and Land-grant Universities. In 2020, IPWatchdog Institute ranked Purdue third nationally in startup creation and in the top 20 for patents. The Purdue Research Foundation is a private, nonprofit foundation created to advance the mission of Purdue University. Contact firstname.lastname@example.org for more information.
About Purdue University
Purdue University is a top public research institution developing practical solutions to today’s toughest challenges. Ranked the No. 5 Most Innovative University in the United States by U.S. News & World Report, Purdue delivers world-changing research and out-of-this-world discovery. Committed to hands-on and online, real-world learning, Purdue offers a transformative education to all. Committed to affordability and accessibility, Purdue has frozen tuition and most fees at 2012-13 levels, enabling more students than ever to graduate debt-free. See how Purdue never stops in the persistent pursuit of the next giant leap at purdue.edu.
Ultrapotent inhibitor of Clostridioides difficile growth, which suppresses recurrence in vivo
George Naclerio, Nader Abutaleb, Daoyi Li, Mohamed Seleem and Herman Sintim
Clostridioides difficile (C. 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, was non-toxic 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 it highlights dramatic drug potency enhancement via halogen substitution.