Synthesis and biological evaluation of a pyoverdin-β-lactam conjugate: A new type of arginine-specific cross-linking in aqueous solution

Abstract

Arginine specific reagents such as phenylglyoxal and other α-dioxo compounds react with arginine side chains by forming adducts with a stoichiometry of 2: 1 or a mixture of 2: 1 and 1: 1. These adducts are labile in neutral and slightly alkaline aqueous solution. We developed a new type of crosslinking reaction with aliphatic β-dioxo compounds. They can be used for the well-defined, irreversible covalent attachment of molecules carrying a primary amino group to arginyl residues of water soluble peptides. The reaction proceeds under mild conditions in aqueous solution, essentially without the formation of side products. A pyoverdin-cephalexin conjugate was synthesized in order to promote its cellular uptake by Pseudomonas aeruginosa. Preliminary biological investigations of the conjugate indicated that it enters the bacterial cell via the pyoverdin-mediated iron uptake pathway.