title: Ellipticines and 9-acridinylamines as inhibitors of D-alanine:D-alanine ligase.
abstract: D-Alanine:D-alanine ligase (Ddl), an intracellular bacterial enzyme essential for cell wall biosynthesis, is an attractive target for development of novel antimicrobial drugs. This study focused on an extensive evaluation of two families of Ddl inhibitors encountered in our previous research. New members of both families were obtained through similarity search and synthesis. Ellipticines and 9-acridinylamines were both found to possess inhibitory activity against Ddl from Escherichia coli and antimicrobial activity against E. coli and Staphylococcus aureus. Ellipticines with a quaternary methylpyridinium moiety were the most potent among all studied compounds, with MIC values as low as 2 mg/L in strains with intact efflux mechanisms. Antimicrobial activity of the studied compounds was connected to membrane damage, making their development as antibacterial drug candidates unlikely unless analogues devoid of this nonspecific effect can be discovered.
authors.affiliation: National Institute of Chemistry, Ljubljana, Slovenia.
authors.forename: Blaž
authors.initials: B
authors.lastname: Vehar
authors.forename: Martina
authors.initials: M
authors.lastname: Hrast
authors.forename: Andreja
authors.initials: A
authors.lastname: Kovač
authors.forename: Janez
authors.initials: J
authors.lastname: Konc
authors.forename: Katherine
authors.initials: K
authors.lastname: Mariner
authors.forename: Ian
authors.initials: I
authors.lastname: Chopra
authors.forename: Alex
authors.initials: A
authors.lastname: O'Neill
authors.forename: Dušanka
authors.initials: D
authors.lastname: Janežič
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D004611:Ellipticines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000588:Amines; D000890:Anti-Infective Agents; D004611:Ellipticines; D004791:Enzyme Inhibitors; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase