• Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis.

      Siebert, David C B; Sommer, Roman; Pogorevc, Domen; Hoffmann, Michael; Wenzel, Silke C; Müller, Rolf; Titz, Alexander; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany. (Beilstein Institut, 2019-01-01)
      The argyrins are secondary metabolites from myxobacteria with antibiotic activity against Pseudomonas aeruginosa. Studying their structure-activity relationship is hampered by the complexity of the chemical total synthesis. Mutasynthesis is a promising approach where simpler and fully synthetic intermediates of the natural product's biosynthesis can be biotechnologically incorporated. Here, we report the synthesis of a series of tripeptide thioesters as mutasynthons containing the native sequence with a dehydroalanine (Dha) Michael acceptor attached to a sarcosine (Sar) and derivatives. Chemical synthesis of the native sequence ᴅ-Ala-Dha-Sar thioester required revision of the sequential peptide synthesis into a convergent strategy where the thioester with sarcosine was formed before coupling to the Dha-containing dipeptide.
    • Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging.

      Wagner, Stefanie; Hauck, Dirk; Hoffmann, Michael; Sommer, Roman; Joachim, Ines; Müller, Rolf; Imberty, Anne; Varrot, Annabelle; Titz, Alexander; HIPS, Helmholtz-Institut für pharmazeutische Forchung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany. (2017-09-28)
      Biofilm formation by pathogenic bacteria is a hallmark of chronic infections. In many cases, lectins play key roles in establishing biofilms. The pathogen Pseudomonas aeruginosa often exhibiting various drug resistances employs its lectins LecA and LecB as virulence factors and biofilm building blocks. Therefore, inhibition of the function of these proteins is thought to have potential in developing "pathoblockers" preventing biofilm formation and virulence. A covalent lectin inhibitor specific to a carbohydrate binding site is described for the first time. Its application in the LecA-specific in vitro imaging of biofilms formed by P. aeruginosa is also reported.
    • Towards the sustainable discovery and development of new antibiotics.

      Miethke, Marcus; Pieroni, Marco; Weber, Tilmann; Brönstrup, Mark; Hammann, Peter; Halby, Ludovic; Arimondo, Paola B; Glaser, Philippe; Aigle, Bertrand; Bode, Helge B; et al. (Springer Nature, 2021-08-19)
      An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.