Discovery of novel peptide dendrimers with potent and broad spectrum of antimicrobial activity
Thissa N. Siriwardena and Jean-Louis Reymond*
University of Bern
Multidrug resistant (MDR) Pseudomonas aeruginosa and Acinetobacter baumannii have been listed, together with Enterobacteriaceae, as the most critical human pathogens by the World Health Organization in 2017. New antibiotics are urgently needed to address MDR bacteria. We recently reported antimicrobial peptide dendrimer (AMPD) G3KL, showing good activity against P. aeruginosa and other Gram-negative strains including MDR clinical isolates.1 We later optimized this dendrimer to a smaller lipidated analog, TNS18, which showed excellent activity against both gram negative and positive bacteria and was also active in a murine infection model against MDR clinical isolates of A. baumannii and E. coli.2 Here we report our latest progress in identifying new AMPD exploiting the concept of chemical space borrowed from small molecule cheminformatics and recently exemplified with bicyclic peptides.3 Our exploration of the dendrimer chemical space led us to the discovery of a more potent analogs of G3KL with an expanded activity range, improved serum stability and very good activity in an in vivo infection model.
1. Stach, M.; Siriwardena, T. N.; Kohler, T.; van Delden, C.; Darbre, T.; Reymond, J. L. Combining Topology and Sequence Design for the Discovery of Potent Antimicrobial Peptide Dendrimers against Multidrug-Resistant Pseudomonas Aeruginosa. Angew. Chem., Int. Ed. 2014, 53, 12827-12831.
2. Siriwardena, T. N.; Stach, M.; He, R.; Gan, B. H.; Javor, S.; Heitz, M.; Ma, L.; Cai, X.; Chen, P.; Wei, D.; Li, H.; Ma, J.; Kohler, T.; van Delden, C.; Darbre, T.; Reymond, J. L. Lipidated Peptide Dendrimers Killing Multidrug-Resistant Bacteria. J. Am. Chem. Soc. 2018, 140, 423-432.
3. Di Bonaventura, I.; Jin, X.; Visini, R.; Probst, D.; Javor, S.; Gan, B.-H. ; Michaud, G.; Natalello, A.; Doglia, S. M.; Kohler, T.; van Delden, C. ; Stocker, A.; Darbre, T.; Reymond, J.-L.; Chem. Sci. 2017, 8, 6784-6798.