Structure-Activity Relationships of Novel Tryptamine-Based Inhibitors of Bacterial Transglycosylase
Autor: | Irena Mlinarič Raščan, Martina Gobec, Eefjan Breukink, Mohammed Terrak, Adeline Derouaux, Izidor Sosič, Marko Anderluh, Matej Sova, Stanislav Gobec, Ana Maria Amoroso |
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Rok vydání: | 2015 |
Předmět: |
Tryptamine
Glycan Staphylococcus aureus Penicillin binding proteins Enterococcus faecium Plasma protein binding Microbial Sensitivity Tests chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Escherichia coli Structure–activity relationship Humans Penicillin-Binding Proteins Peptidoglycan glycosyltransferase biology Lipid II Escherichia coli Proteins Serine-Type D-Ala-D-Ala Carboxypeptidase Tryptamines Uridine Diphosphate N-Acetylmuramic Acid Anti-Bacterial Agents HEK293 Cells chemistry Biochemistry biology.protein Molecular Medicine Methicillin Resistance Peptidoglycan Peptidoglycan Glycosyltransferase Protein Binding |
Zdroj: | Journal of medicinal chemistry. 58(24) |
ISSN: | 1520-4804 |
Popis: | Penicillin-binding proteins represent well-established, validated, and still very promising targets for the design and development of new antibacterial agents. The transglycosylase domain of penicillin-binding proteins is especially important, as it catalyzes polymerization of glycan chains, using the peptidoglycan precursor lipid II as a substrate. On the basis of the previous discovery of a noncovalent small-molecule inhibitor of transglycosylase activity, we systematically explored the structure-activity relationships of these tryptamine-based inhibitors. The main aim was to reduce the nonspecific cytotoxic properties of the initial hit compound and concurrently to retain the mode of its inhibition. A focused library of tryptamine-based compounds was synthesized, characterized, and evaluated biochemically. The results presented here show the successful reduction of the nonspecific cytotoxicity, and the retention of the inhibition of transglycosylase enzymatic activity, as well as the ability of these compounds to bind to lipid II and to have antibacterial actions. |
Databáze: | OpenAIRE |
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