The novel lipopeptide antibiotic A21978C complex is active against Gram-positive organisms. This complex consists of a common peptide nucleus with various lipid acyl groups at the N-terminus characteristic of each individual factor. The fatty acid acyl group is removed by incubation of the A21978C complex with Actinoplanes utahensis to give the peptide nucleus. This peptide nucleus has the same amino acid sequence as A21978C. New analogs of A21978C were synthesized by acylation of the N-terminus of a tert-butoxycarbonyl (tert-BOC)-protected nucleus and subsequent deprotection. 1H NMR showed that the newly introduced acyl group was at the desired N-terminus. Three major groups of analogs were synthesized bearing fatty acid acyl, amino-aroyl and extended peptide side chains. Each analog was evaluated for antimicrobial activity and acute toxicity. Of these analogs, the n-decanoyl analog of A21978C (LY146032) gave the best survival in the mouse acute toxicity test at a high dose of 1,000 mg/kg, iv and was chosen for further study. This analog has been named daptomycin.