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J Bacteriol. 1968 June; 95(6): 2139-2150
Copyright © 1968 American Society for Microbiology. All Rights Reserved.

Actinomycin Analogues Containing Pipecolic Acid: Relationship of Structure to Biological Activity

Department of Microbiology, Georgetown University Schools of Medicine and Dentistry, Washington, D.C. 20007
Laboratory of Biology of Viruses, National Institutes of Health, Bethesda, Maryland 20014

ABSTRACT

Streptomyces antibioticus synthesizes a mixture of actinomycins which differ at the "imino acid" site of the peptide chains. In the presence of exogenous pipecolic acid, several new actinomycins were synthesized and 70% of the proline in the antibiotic mixture was replaced by the analogue. Three new antibiotics (designated Pip 1, Pip 1ß, and Pip 2) were isolated from culture filtrates, purified, and crystallized. The molar ratio of pipecolic acid to proline was: Pip 1, 1:0; Pip 1ß, 1:1; Pip 2, 2:0. These compounds inhibited the growth and cell division of gram-positive, but not gram-negative, bacteria. The relative inhibitory activity against bacteria, Escherichia coli deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase in vitro, and RNA synthesis in Bacillus subtilis and mouse L-929 cells was: actinomycin IV = Pip 1ß > Pip 2 > Pip 1. Protein synthesis in B. subtilis was less affected, and DNA synthesis was inhibited only at higher concentrations of antibiotic tested. In L cells, DNA formation was reduced less than RNA synthesis, whereas protein synthesis was not blocked under the experimental conditions employed. Kinetic studies with B. subtilis revealed that RNA synthesis was inhibited rapidly followed by an inhibition of protein synthesis. All four antibiotics markedly inhibited the replication of vaccinia virus and reovirus in tissue culture cells, but the production of poliovirus was resistant to the antibiotics. These actinomycins bind to DNA, resulting in an elevation of its T_m and a decrease in the peak extinction of the actinomycins. The mode of action, as well as the structure-activity relationships among the actinomycins, are discussed relative to a previously proposed model of binding.

¹ Present address: Laboratory of Pediatric Virology, Department of Pediatrics, Georgetown University Hospital, Washington, D.C. 20007.