Effect of a diazaborine derivative (Sa 84.474) on the virulence of Escherichia coli.

The scope of selective inhibition of lipopolysaccharide (LPS) biosynthesis in virulent organisms with a diazaborine derivative (Sa 84.474) as a means to render them avirulent was explored. A serum resistant Escherichia coli 0111:B4 became serum sensitive following its cultivation in vitro in media containing 1.5 mg/l of Sa 84.474, a concentration shown previously to inhibit over 95% of normal LPS biosynthesis in its mutant J5 strain. An encapsulated E. coli 01:K1 was also converted to serum sensitivity. In addition, Sa 84.474-pretreatment increased the efficiency with which the previously resistant organisms were opsonized in normal human serum and subsequently phagocytosed by granulocytes. In vivo, intravenously inoculated, Sa 84.474-pretreated bacteria were rapidly removed from the blood circulation and were significantly (P less than 0.05) less virulent in inducing lethal peritoneal infections in mice (LD50 4.9 +/- 1 X 10(6) cfu) when compared to untreated control bacteria (LD50 2.2 +/- 0.97 X 10(6) cfu). The results suggest that the LPS plays an important role in the virulence of the two bacterial strains and imply that agents acting in a similar manner but with acceptable selective toxicity might be novel drugs for therapy of Gram-negative bacterial infections.