The preparation of alanine peptides of erythromycin A.

Erythromycin A(1)inhibits the growth of bacteria by blocking protein synthesis.1) The antibiotic acts by specifically binding to 50 S ribosomes in both Gram-positive(Bacillus2)and Staphylococcus3)) and Gram-negative(Eschericihac4))bacteria. In cell free preparations, the binding occurs at very low erythromycin concentrations and about one molecule of erythromycin is bound per 50 S ribosome.3・4) However, against whole cells antibacterial activity of erythromycin is limited to Gram-positive bacteria because of its inability to penetrate the outer membrane of many Gram-negatives. If a means of facili. tating transport into Gram-negative cells could be discovered, erythromycin would presumably be fully active. We wish to report an attempt to confer Gram-negative activity on erythromycin A and 9.(S)一erythromycylamine by attachment of alanine peptides. An easily accessible site fbr attachment of peptides is the desosamine hydroxyl by an ester linkage. Erythromycin 2'-esters are well absorbed orally but must hydrolyze in vivo to be therapeutically effective.5) Treatment oferythromycin A wlth carbobenzy1oxy-L-alanine in the presence of dicyclohexylcarbodiimide(DCC)followed by hydrogenolysis of the