TY - JOUR
T1 - Design, Synthesis, and Evaluation of Cephamycin-Based Antisporulation Agents targeting Clostridioides difficile
AU - Cun, Wendy Y.
AU - Bate, Clara E.
AU - Srikhanta, Yogitha N.
AU - Hutton, Melanie L.
AU - Webb, Chaille T.
AU - Revitt-Mills, Sarah A.
AU - Lyras, Dena
AU - McGowan, Sheena
AU - Yu, Haibo
AU - Keller, Paul A.
AU - Pyne, Stephen G.
N1 - Funding Information:
This research was funded by National Health and Medical Research Council of Australia, grant number 1145760. The antimicrobial screening performed by CO-ADD (The Community for Antimicrobial Drug Discovery) was funded by the Wellcome Trust (UK) and The University of Queensland (Australia). Computational resources were generously provided by the National Computational Infrastructure through the NCMAS and UOW-NCI schemes.
Publisher Copyright:
© 2023 American Chemical Society
PY - 2024/1/11
Y1 - 2024/1/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85176567480&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c01662
DO - 10.1021/acs.jmedchem.3c01662
M3 - Article
C2 - 38112278
AN - SCOPUS:85176567480
SN - 0022-2623
VL - 67
SP - 450
EP - 466
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -