Synthesis and Antimicrobial Activity of Albicidin Derivatives with Variations of the Central Cyanoalanine Building Block. (1st June 2016)

• Record Type: Journal Article
• Authors: Grätz, Stefan; Kerwat, Dennis; Kretz, Julian; von Eckardstein, Leonard; Semsary, Siamak; Seidel, Maria; Kunert, Maria; Weston, John B.; Süssmuth, R. D.
• Is Part Of: ChemMedChem. Volume 11:Number 14(2016)
• Page Start: 1499
• Page End: 1502
• Publication Date: 2016-06-01
• Subjects: albicidin -- antibiotics -- gyrase -- peptides -- structure–activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600163
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Improving drug‐likeness : Albicidin is a new antibacterial lead structure. To investigate the pharmacophore regions of the structure we chose the central α‐amino acid to be substituted. The bioactivity of the newly synthesized derivatives was determined, and the threonine‐containing derivative shows superior target inhibition. These results will aid our understanding of the detailed mode of action and will help to improve the pharmacological and physicochemical properties of albicidin.