Design of New Polymyxins with Reduced Nephrotoxicity

There is a clear unmet medical need in the field of infectious diseases: infections caused by resistant bacteria. A major goal to fight resistant bacteria involves the design, discovery and development of new antibiotics particularly against multi-drug-resistant strains. Polymyxins, an old class of antimicrobial cyclic lipopeptides highly potent against therapeutically relevant Gram-negative bacteria, have been rescued and are now used only as last resort antibiotics in hospitals because of their nephrotoxicity and neurotoxicity that require careful monitoring of the patient. Our group has embarked in a project to design and develop new polymyxins devoid of toxicity problems using a versatile and chemically accessible scaffold structure^[1,2]. Compounds show a remarkable activity against Gram-negative bacteria. Synergistic and antibiofilm activities have also been recently described in combination with imipenem^[3]. Herein, the last results of our recently designed polymyxin analogs will be presented.

References

1. F. Rabanal, A. Grau-Campistany, X. Vila-Farrés, J. Gonzalez-Linares, M. Borràs, J. Vila, A. Manresa and Y. Cajal. A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity, Sci. Rep., 2015, 5, 10558. https://www.nature.com/articles/srep10558
2. F. Rabanal, Y. Cajal, Recent advances and perspectives in the design and development of polymyxins. Natural Product Reports, 34, 886 - 908 (2017) http://pubs.rsc.org/en/content/articlelanding/2017/np/c7np00023e#!divAbstract  
3. H. Rudilla, E. Fusté, Y. Cajal, F. Rabanal, T. Vinuesa and M. Viñas, Synergistic Antipseudomonal Effects of Synthetic Peptide AMP38 and Carbapenems, Molecules, 2016, 21, 1223. http://www.mdpi.com/1420-3049/21/9/1223