Antimicrobial peptide dendrimers against multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii with enhanced angiogenic effect

Abstract

Multi-drug resistant bacteria represent a major public health threat. In particular, Gram-negative pathogens such as Pseudomonas aeruginosa are responsible for significant morbidity and mortality in hospitals, making it urgent to develop new classes of antimicrobials. Peptide based antimicrobials offer an attractive opportunity to control these pathogens]. We have developed potent antimicrobial peptides with a branched structure (peptide dendrimers) with high activity against multi-resistant clinical isolates of P. aeruginosa and Acinetobacter baumanii by screening a third generation peptide dendrimer library. Our best compound G3KL is composed of natural L-lysine and L-leucine residues (37 amino acid residues in total) linked by amide bonds but due to the branched topology it is stable to serum proteases in contrast to linear peptides to red blood cells and, in contrast to linear AMPs, stability and high activity in human serum.1 The activity of G3KL (MIC values) is 4-8 mg/ml for a large panel of P. aeruginosa and A. baumannii resistant strains.2 The antimicrobial G3KL showed low toxicity to red blood cells (MHC of 1000 mg/ml), CHO and epitelial cells. We have also showed that peptide dendrimers such as G3KL exert direct potent pro-angiogenic effects and can be incorporated in biolofical bandage formulation to improve the healing process in severe burn wounds.3 1. Combining topology and sequence design for the discovery of potent antimicrobial peptide dendrimers against multidrug-resistant Pseudomonas aeruginosa. Stach M, Siriwardena T N, Köhler T, van Delden C, Darbre T, Reymond J-L. Angew Chem Int Ed. 2014, 53, 12827-31. 2. In Vitro Activity of a Novel Antimicrobial Peptide Dendrimer (G3KL) Against Multidrug-Resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Pires J, Siriwardena T N, Stach M, Tinguely R, Kasraian S, Luzzaro F, Leib S L, Darbre T, Reymond J-L, Endimiani A.,. Antimicrob. Agents Chemother., 2015, 59, 7915-7918. 3. Anti-Microbial Dendrimers against Multidrug-Resistant P. aeruginosa Enhance the Angiogenic Effect of Biological Burn-wound Bandages. Abdel-Sayed P, Kaeppli A, Siriwardena T, Darbre T, Perron K, Jafari P, Reymond J-L, Pioletti D P, Applegate L A, Sci. Rep., 2016, doi:10.1038/srep22020