Discovery and Development of antisense therapeutics for Clostridioides difficile infection

Clostridioides difficile is the leading cause of nosocomial infections and antibiotic-associated diarrhea. The incidence and severity of C. difficile infections (CDI) have dramatically increased due to the overuse of antibiotics and the emergence of hypervirulent epidemic strains, which were responsible for several outbreaks globally. Even though the overuse of antibiotics is responsible for CDI, the management of CDI requires antibiotic administration. Consequently, the drawbacks associated with the current anti-CDI therapeutic arsenal highlights the critical need for developing novel strategies for the treatment of CDI and the prevention of CDI recurrence. An alternative strategy for developing novel therapeutics involves the exploitation of antisense oligomers (ASOs), such as peptide nucleic acids (PNAs) that suppress essential genes in bacterial pathogens. This research project focuses on developing targeted therapeutics to disarm virulence factors and suppress gene expression in C. difficile. Building on our successful use of antisense technology in C. difficile, we aim to investigate the potential and implication of inhibiting critical pathways within C. difficile. These pathways include transcription and translation machinery, protein translocation machinery, cell division, replication, and fatty acid synthesis. We are also planning on assessing the toxicity and in vivo efficacy in murine models of CDI and its recurrence. We believe the narrow spectrum and precision targeting of these antisense therapeutics provide an innovative new approach that selectively eliminate problematic pathogens, such as C. difficile without harming the healthy human gut microbiota. Altogether, these studies are of paramount importance and have the potential to make a significant impact, effectively leapfrogging the traditional drug development process. Project Number: 1R21AI190710-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Mohamed Seleem | Institution: VIRGINIA POLYTECHNIC INST AND ST UNIV, BLACKSBURG, VA | Award Amount: $437,541 | Activity Code: R21 | Study Section: Drug Discovery and Molecular Pharmacology A Study Section [DMPA] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19071001A1