Download MendeleyStructure-Activity Relationship and Crystallographic Study of New Monobactams.
Kavas, V., Contreras-Martel, C., Pajk, S., Knez, D., Martins, A., Gould, T.A., Roper, D.I., Zdovc, I., Dessen, A., Hrast Rambaher, M., Gobec, S.(2026) J Med Chem
- PubMed: 41632911
- DOI: https://doi.org/10.1021/acs.jmedchem.5c02427
- Primary Citation of Related Structures:
9SG5, 9SG6, 9SG7, 9SG8, 9SG9, 9SGA, 9SGB, 9SGC, 9SGD, 9SGE - PubMed Abstract:
Monobactams, a subclass of β-lactam antibiotics with a monocyclic scaffold, are uniquely resistant to hydrolysis by metallo-β-lactamases, providing a distinct therapeutic advantage. Here, we report an in silico -based structure-activity relationship (SAR) investigation of aztreonam-related monobactams. A focused library of monobactam derivatives was synthesized and evaluated for inhibition of penicillin-binding proteins (PBPs) and antibacterial activity. Ten compounds, including aztreonam, were crystallized with truncated PBP1b from Streptococcus pneumoniae , used as a model PBP. Potent PBP1b inhibitors were developed, although high enzymatic potency was not always reflected in strong antibacterial activity. Certain derivatives showed activity against Staphylococcus aureus , which is typically resistant to monobactams. 2D similarity search identified potent inhibitors active against Escherichia coli , Klebsiella pneumoniae , and Acinetobacter baumannii . Crystal structures revealed previously unrecognized binding interactions, including a halogen bond with a conserved threonine residue, underscoring the potential of these interactions to support the development of more potent PBP inhibitors.
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
Organizational Affiliation:
