Inhibition of arabinose 5-phosphate isomerase. An approach to the inhibition of bacterial lipopolysaccharide biosynthesis

Abstract

Arabinose 5-phosphate (A5P) isomerase is a key enzyme in the biosynthesis of lipopolysaccharide, an essential component of the outer membrane of gram-negative bacteria. The mechanism of the isomerase is envisioned to involve an enediol intermediate. A series of analogs of the substrates or intermediate were tested as inhibitors of A5P isomerase with the belief that a good inhibitor would stop bacterial growth or render the cells more susceptible to other antibiotics or natural defenses. In a series of phosphorylated sugars, the order of isomerase inhibitory activity was as follows: aldonic acids > alditols > aldoses. Nonphosphorylated sugars were much less inhibitory. The best inhibitor was erythronic acid 4-phosphate, which had Km/Ki = 29. None of the compounds displayed antibacterial activity in vitro.