Targeting lipopolysaccharides by the nontoxic polymyxin B nonapeptide sensitizes resistant Escherichia coli to the bactericidal effect of human neutrophils

Abstract

The nonapeptide of polymyxin B (PMBN) has been reported to sensitize various pathogenic gram-negative bacteria to the direct bactericidal effect of human serum. To investigate the impact of PMBN on human neutrophil- effected killing of the serum- and phagocytosis-resistant Escherichia coli strains C14 and O111, serum was coapplied with PMBN or with neutrophils, but this did not result in decreased numbers of viable bacteria. In contrast, the most potent bacterial killing occurred in the presence of neutrophils plus serum components plus PMBN. The effect of this on E. coli C14 was the appearance of inositol phosphates, diacylglycerol, respiratory burst, elastase liberation, and generation of lipid mediators (leukotriene B'S'U'B'4, 5-HETE, and platelet-activating factor). Strong neutrophil activation required early, but not late, complement components and was blocked by inhibition of phagocytosis with cytochalasin D. PMBN seems to cause dramatic support of natural host defense by complement-dependent sensitization of E. coli to the bactericidal efficacy of human neutrophils.