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The novel lipopeptide antibiotic A21978C complex is active against Gram-positive organisms. This complex consists of a commonpeptide nucleus with various lipid acyl groups at the iV-terminus characteristic of each individual factor. The fatty acid acyl group is removed by incubation of the A21978Ccomplex with Actinoplanes utahensis to give the peptide nucleus. This peptide nucleus has the same amino acid sequence as A21978C. New analogs of A21978Cwere synthesized by acylation of the iV-terminus of a ter/-butoxycarbonyl (ter/-BOC)-protected nucleus and subsequent deprotection. XHNMRshowed that the newly introduced acyl group was at the desired iV-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 «-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.

A54145 complex is made up of eight factors; A, A1? B, B1? C, D, E, and F which were active in vitro (MIC 0.25~> 32/ig/ml) against Gram-positive aerobic organisms. The complex, factors B and Bj were found to be active against two strains of Clostridium perfringens. A calcium dependence study on someof the factors showed that their in vitro antibacterial activity was greatly enhanced by the presence of calcium (50mg/liter) in the media. Resistance build-up was seen when Staphylococcus sp. and Streptococcus sp. were passed seven times in the presence of sublethal concentrations of A54145antibiotics. This resistance disappeared immediately when the resistant organisms were passed in the absence of the antibiotics. Factor A was very effective against Staphylococcus aureus and Streptococcuspyogenes infections in mice (sc ED5Osof 3.3~2.4 mg/kg x 2, respectively). Factor B was more active against S. pyogenes in vivo (sc ED50, 0.9mg/kg x 2). Acute mousetoxicities were determined with these antibiotics. Semisynthetic derivatives were evaluated.

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