Synthesis of Albicidin Derivatives: Assessing the Role of N‐terminal Acylation on the Antibacterial Activity

• DOI: 10.1002/cmdc.201600231
• Publication Date: 2016-07-21T11:17:11Z
• Authors: Dennis Kerwat; Stefan Grätz; Julian Kretz; Maria Seidel; Maria Kunert; John B. Weston; Roderich D. Süssmuth
• Keywords: Structure-Activity Relationship; Xanthomonas; Dose-Response Relationship, Drug; Molecular Structure; Acylation; Microbial Sensitivity Tests; Organic Chemicals; 01 natural sciences; Anti-Bacterial Agents; 0104 chemical sciences

AbstractThe peptide antibiotic albicidin, which is synthesized by the plant pathogenic bacterium, Xanthomonas albilineans, represents the most prominent member of a new class of antibacterial gyrase inhibitors. It shows remarkable antibacterial activities against Gram‐positive and Gram‐negative microorganisms. Its unique structure potentially represents a new lead structure for the development of an antibacterial drug. Here we report the synthesis of 14 albicidin derivatives with structural variations at the N‐terminus, primarily investigating the effects of variation of cinnamoyl, phenylpropanoyl, and benzoyl residues. Gyrase inhibition in vitro and determination of minimal inhibitory concentrations were assessed in parallel. Activities in a nanomolar range and the importance of N‐acylation were demonstrated.