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.

Over eighty iV-alkyl vancomycins were synthesized by reductive alkylation of vancomycin with the appropriate aldehydes. The 7V-alkyl vancomycins exhibit greater antibacterial activity than the corresponding iV-acyl vancomycins and the parent antibiotic.Some of these semisynthetic vancomycins are five times more active than vancomycin. The AT-alkyl vancomycins also show longer elimination half-lives in rats than vancomycin.For the past 30 years, vancomycin has been the drug of choice to treat severe Gram-positive infections caused by methicillin-resistant Staphylococcus aureus. Recent reports have described glycopeptides with acylamido side chains on a sugar residue,2~6) and some of these compounds, e.g. teicoplanin, have been claimed to have more favorable antibacterial and pharmacokinetic properties than vancomycin.70 Synthesis of several iV-acyl vancomycins and structure activity relationship studies revealed no substantial advantage of these iV-acyl vancomycins over the parent antibiotic.8) As an extension to the structure-activity relationship (SAR) of the iV-acyl vancomycin research, we undertook the synthesis and evaluation of iV-alkyl vancomycins. ChemistryThe AT-alkyl vancomycins were obtained by reductive alkylation of vancomycin with the appropriate aldehydes. This reaction could yield two mono-7V-alkyl derivatives substituted at the amino groups of vancosamine sugar and iV-methyl leucine residue, respectively, and one di-N-alkyl vancomycin. The reaction products were monitored by analytical HPLC. Not all reactions produced all the three possible products. However, if all three iV-alkyl vancomycins were available in a series, the retention times of the iV-alkyl vancomycins were diagnostic of the site of alkylation as previously observed for the iV-acyl derivatives.50 The mono-iV-alkyl derivative substituted on vancosamine eluted first, then the second mono-iV-alkyl vancomycin functionalized on JV-methyl leucine, and finally the di-iV-alkyl vancomycin (see Table 1).The ratio of the three 7V-alkyl vancomycins from the reductive alkylation reaction depended on the reaction conditions which could be adjusted to yield the desired iV-alkyl derivative as the major product. The reaction mixture was purified by preparative HPLC.The structures of the iV-alkyl vancomycins were confirmed by fast atom bombardment mass spectrometry (FAB-MS). The molecular ion indicates if the derivatives is a mono-or di-iV-alkyl vancomycin. The fragmentation pattern of the mono-7V-alkyl derivative clearly establishes the site of substitution between the two alternative amino groups in vancomycin. Thus, the mono-iV-alkyl vancomycin alkylated on the JV-methyl leucine affords the disaccharide, vancosaminyl-O-glucose and vanf Seerefl.

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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A series of 20-deoxo-20-cyclic (alkylamino) derivatives of tylosin, desmycosin, macrocin and lactenocin was prepared by reductive amination of the C-20 aldehyde group. The majority of the compounds were prepared using metal hydrides (sodium cyanoborohydride or sodium borohydride) as the reducing agents and a suitable cyclic alkylamine. Subsequently, a more convenient procedure was developed using formic acid as a reducing agent. The C-20 amino derivatives prepared from desmycosin exhibited good in vitro antimicrobial activity against Pasteurella haemolytica and Pasteurella multocida (MIC range of 0.78~6.25^g/ml) as well as Mycoplasma species (MIC range of 0.39~6.25^g/ml). Several derivatives showed excellent oral efficacy against infections caused by P. multocida in chicks, One of these