2. Academic Validation
  3. Design, Synthesis, and Evaluation of Cephamycin-Based Antisporulation Agents targeting Clostridioides difficile

Design, Synthesis, and Evaluation of Cephamycin-Based Antisporulation Agents targeting Clostridioides difficile

  • J Med Chem. 2024 Jan 11;67(1):450-466. doi: 10.1021/acs.jmedchem.3c01662.
Wendy Y Cun 1,  Clara E Bate 2 3,  Yogitha N Srikhanta 2 3,  Melanie L Hutton 2 3,  Chaille T Webb 2 3,  Sarah A Revitt-Mills 2 3,  Dena Lyras 2 3,  Sheena McGowan 2 3,  Haibo Yu 1 4,  Paul A Keller 1,  Stephen G Pyne 1
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Bioscience, Molecular Horizons Research Institute, University of Wollongong, Wollongong 2522 New South Wales, Australia.
  • 2 Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton 3800, Victoria, Australia.
  • 3 Centre to Impact AMR, Monash University, Clayton 3800, Victoria Australia.
  • 4 ARC Centre of Excellence in Quantum Biotechnology, University of Wollongong, Wollongong 2522 New South Wales, Australia.
PMID: 38112278 DOI: 10.1021/acs.jmedchem.3c01662
Abstract

With the aim of discovering small molecule inhibitors of the sporulation process in Clostridioides difficile, we prepared a series of C-7 α-(4-substituted-1H-1,2,3-triazol-1-yl)acetamide analogues of cefotetan, a known inhibitor of the C. difficile sporulation-specific protein target CdSpoVD. These analogues were evaluated using both in vitro binding assays with CdSpoVD and antisporulation assays against C. difficile. Further design concepts were aided utilizing the predicted docking scores (DS) using both AlphaFold (AF) models, and a crystal structure of the CdSpoVD protein (PDB 7RCZ). Despite being 1 order of magnitude more potent as a sporulation inhibitor than cefotetan, in vivo studies on compound 6a in a murine-model of C. difficile Infection demonstrated comparable spore shedding capabilities as cefotetan. Importantly, compound 6a had no concerning broad spectrum Antibacterial activities, toxicity, or hemolytic activity and thus has potential for further drug development.

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