Using an alanine-scanning method, we have found that the antibacterial and hemolytic activities of the amphipathic cyclic decapeptide antibiotic tyrocidine A depend on different structural components. Single substitution of glutamine-6 of the natural product with a cationic amino acid results in a therapeutic index enhancement of up to 140-fold. Successful dissociation of the two intimately associated properties should enable discovery of novel analogues with both high bacterial selectivity and antibacterial potency to counter microbial resistance.

A simple and efficient preparation of gramicidin S and its analogues is described. It involves solid-phase peptide synthesis and on-resin macrolactamization without side chain protection, affording cyclic products in high yield and high purity. The high specificity of the cyclization reaction was shown to originate in the formation of a pre-organized conformation of the linear biosynthetic precursor of gramicidin S. This facile method will provide convenient access to the analogues of the natural product for functional optimization to counter microbial resistance.

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