A diazaborine derivative inhibits lipopolysaccharide biosynthesis

Abstract

Inhibitors of the biosynthesis of peptidoglycan, the rigid layer of the bacterial cell wall which is responsible for the shape of the cell, are among the most effective antibacterial agents known. Both Gram-positive and Gram-negative organisms are susceptible to the action of such compounds. As lipopolysaccharide (LPS) is an integral part of the outer membrane of Gram-negative bacteria, it is possible that a blockage of its biosynthesis might result in the arrest of cellular growth and eventually cell death, analogous to the effects seen with inhibitors of peptidoglycan biosynthesis. However, no antibacterial agent has been described which inhibits growth in this way. We present here experimental evidence which indicates that 1,2-dihydro-1-hydroxy-6-methyl-2-(propanesulphonyl)-thieno(3,2-D) (1,2,3)-diazaborine (code no. 84474), a heterocyclic, boron-containing substance, prevents bacterial proliferation by inhibiting LPS biosynthesis. There was a reduction in galactose incorporation into the LPS of whole cells, and no newly formed LPS chains appeared in whole bacteria in the presence of the compound, as demonstrated by electron microscopy. The 2-keto-3-deoxy-octonate metabolism seems to be the target of 84474 as arabinose 5-phosphate incorporation into macro-molecular material was affected.