title: Structure-Activity Relationships of Novel Tryptamine-Based Inhibitors of Bacterial Transglycosylase.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Izidor
authors.initials: I
authors.lastname: Sosič
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Anderluh
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Matej
authors.initials: M
authors.lastname: Sova
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Gobec
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Irena
authors.initials: I
authors.lastname: Mlinarič Raščan
authors.affiliation: Centre d'Ingénierie des Protéines, Université de Liège , Allée de la Chimie, B6a, B-4000, Sart Tilman, Liège, Belgium.
authors.forename: Adeline
authors.initials: A
authors.lastname: Derouaux
authors.affiliation: Centre d'Ingénierie des Protéines, Université de Liège , Allée de la Chimie, B6a, B-4000, Sart Tilman, Liège, Belgium.
authors.forename: Ana
authors.initials: A
authors.lastname: Amoroso
authors.affiliation: Centre d'Ingénierie des Protéines, Université de Liège , Allée de la Chimie, B6a, B-4000, Sart Tilman, Liège, Belgium.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Terrak
authors.affiliation: Department Biochemistry of Membranes, Bijvoet Centre, Institute of Biomembranes, Utrecht University , Utrecht 3584 CH, The Netherlands.
authors.forename: Eefjan
authors.initials: E
authors.lastname: Breukink
authors.affiliation: Faculty of Pharmacy, University of Ljubljana , Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D016984:Enterococcus faecium / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors*; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase / Q000037:antagonists & inhibitors*; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D046915:Penicillin-Binding Proteins; D014363:Tryptamines; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; D046928:Peptidoglycan Glycosyltransferase; C478681:penicillin-binding protein 1B, E coli; D046929:Serine-Type D-Ala-D-Ala Carboxypeptidase