title: Synthesis and Antimicrobial Activity of Albicidin Derivatives with Variations of the Central Cyanoalanine Building Block.
abstract: To investigate the pharmacophore regions of the antibiotic albicidin, derivatives with variations on the central amino acid were synthesized. Charged as well as uncharged residues were chosen to explore the influence of charge, chirality, and steric bulk. The bioactivity of the newly synthesized derivatives was determined by a microdilution technique to obtain minimum inhibitory concentrations (MIC) values. The compounds were also tested in a cell-free system to obtain information about their ability to inhibit their primary target, DNA gyrase. It was then shown that derivatives with uncharged side chains retain antibacterial activity, whereas incorporation of charged amino acid residues decreases the antibacterial activity dramatically, possibly due to restricted cell penetration of these derivatives. From the newly synthesized derivatives, the threonine derivative shows the most promising results in both tests. The information will help to develop the features of albicidin toward more drug-like structures.
authors.affiliation: Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Grätz
authors.affiliation: Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Kerwat
authors.affiliation: Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Kretz
authors.affiliation: Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany.
authors.forename: Leonard
authors.initials: L
authors.lastname: von Eckardstein
authors.affiliation: Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany.
authors.forename: Siamak
authors.initials: S
authors.lastname: Semsary
authors.affiliation: Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Seidel
authors.affiliation: Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kunert
authors.affiliation: Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany.
authors.forename: John B
authors.initials: JB
authors.lastname: Weston
authors.affiliation: Institut für Organische Chemie, Technische Universität Berlin, Straße des 17. Juni 124, 10623, Berlin, Germany. suessmuth@chem.tu-berlin.de.
authors.forename: R D
authors.initials: RD
authors.lastname: Süssmuth
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D027081:DNA Gyrase / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects; D016982:Micrococcus luteus / Q000187:drug effects; D009930:Organic Chemicals / Q000138:chemical synthesis / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D014974:Xanthomonas
chemical_list: D000890:Anti-Infective Agents; D009930:Organic Chemicals; D059005:Topoisomerase II Inhibitors; C046156:albicidin; D027081:DNA Gyrase; D000409:Alanine
keywords: albicidin; antibiotics; gyrase; peptides; structure-activity relationships