Synthesis and Bioactivity Investigation of the Individual Components of Cyclic Lipopeptide Antibiotics

In this paper, 26 natural polymyxin components and a new derivative S-2 were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E-2, E-2-Val, A(2), M-2, D-2, and S-2 showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E-2, M-2, and S-2 was similar to that of polymyxin E. Compound S-2, with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S-2 could be a new drug candidate.