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.
Lam
C
C
Turnowsky
F
F
Högenauer
G
G
Schütze
E
E
D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity*; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000096:biosynthesis*; D008163:Luminescent Measurements; D051379:Mice; D010587:Phagocytosis
D001896:Boron Compounds; D008070:Lipopolysaccharides; C032255:1,2-dihydro-1-hydroxy-6-methyl-2-(propanesulfonyl)-thieno(3,2D)(1,2,3)-diazaborine