On the transport of tripeptide antibiotics in bacteria

Article abstract of DOI:10.1111/j.1432-1033.1976.tb10420.x

The two tripeptide antibiotics L 2 amino 4 methylphosphinobutyryl alanyl alanine (L phosphinothricyl alanyl alanine) and L (N⁵ phosphono)methionine S sulfoximinyl alanyl alanine, both inhibitors of the glutamine synthetase, are transported into the cell of Escherichia coli K 12 via the oligopeptide transport system. The uptake by this system is proved first of all by cross resistance with tri L ornithine using oligopeptide transport deficient mutants, and secondly by antagonism tests demonstrating competitive reversal of the action of the antibiotic by several peptides which have been shown to be transported via the oligopeptide transport system, e.g. tri L alanine, tetra L alanine, tri L lysine, tri L serine, tri glycine, glycyl glycyl L alanine and the synthetic tripeptide L azaadenylaminohexanoyl alanyl alanine. On the other hand, there is no effect on the action of the antibiotic in antagonism tests with compounds which use different transport systems, such as L alanyl alanine, L lysyl lysine, glutathione and the synthetic amino acid azaadenylaminohexanoic acid, i.e. 2 amino 6 (7 amino 3H v triazolo [4,5 d] pyrimidin 3 yl)hexanoic acid. Another inhibitor of the glutamine synthetase, L methionine S dioxide (methioninesulfone) could be converted into a tripeptide form by linkage to L alanyl alanine analogously to the tripeptide antibiotics described above. Whereas the free L methionine S dioxide seems to be transported via the methionine transport system, the tripeptide form is transported via the oligopeptide transport system. Thus, this glutamine synthetase inhibitor can be taken up by the cell via two different transport mechanisms. These results indicate that this could provide a synergistic effect. The syntheses of the new tripeptides L azaadenylaminohexanoyl alanyl alanine and L methionine S dioxidyl alanyl alanine were performed by dicyclohexylcarbodiimide couplings of the unusual N protected L α amino acids azaadenylaminohexanoic acid and L methionine S dioxide to L alanyl alanine tert butyl ester followed by common deprotection steps. Tri L ornithine was synthesized without carboxyl protection via two successive couplings of hydroxybenzotriazol esters of N(α)butoxycarbonyl N(δ)benzyloxycarbonyl L ornithine to N(δ)benzyloxycarbonyl L ornithine.