Rational design of bacitracin A derivatives by incorporating natural product derived heterocycles.
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.
Wagner
Björn
B
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany.
Schumann
Dirk
D
Linne
Uwe
U
Koert
Ulrich
U
Marahiel
Mohamed A
MA
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
D000900:Anti-Bacterial Agents; D001685:Biological Factors; D006571:Heterocyclic Compounds; D013844:Thiazoles; D001414:Bacitracin; C026461:bacitracin A