title: Rational design of bacitracin A derivatives by incorporating natural product derived heterocycles.
abstract: Heterocycles display common structural motifs in nonribosomally produced peptides with an enormous impact on their bioactivity. In the case of the branched cyclic Bacitracin A, the thiazoline moiety is manufactured during NRPS peptide chain elongation. Here we describe a method to selectively alter the heterocyclic metal binding subunit of Bacitracin A by the synthesis of heterocyclic building blocks that were successfully coupled to the linear decapeptide and subsequently cyclized using the excised bacitracin PCP-TE bidomain. Utilization of this cyclase allowed the first generation of branched cyclic bacitracin derivatives containing thiazole and oxazoles. The generated bacitracin derivatives showed bactericidal activity, indicating the possibility of altering the biological important heterocyclic subunit and overcoming existing limitations for the application of bacitracin.
authors.affiliation: Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Wagner
authors.forename: Dirk
authors.initials: D
authors.lastname: Schumann
authors.forename: Uwe
authors.initials: U
authors.lastname: Linne
authors.forename: Ulrich
authors.initials: U
authors.lastname: Koert
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Marahiel
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001412:Bacillus subtilis / Q000187:drug effects; D001414:Bacitracin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001685:Biological Factors / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001685:Biological Factors; D006571:Heterocyclic Compounds; D013844:Thiazoles; D001414:Bacitracin; C026461:bacitracin A