| Institution: | 1. Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany;2. Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany
These authors contributed equally to this work.;3. Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany;4. PharmBioTec GmbH, 66123 Saarbrücken, Germany;5. Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany;6. Institute of Organic Chemistry, Leibniz University of Hannover, Schneiderberg 1B, 30167 Hannover, Germany |
| Abstract: | Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids—a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria. |
