Purification, toxicity, and antiendotoxin activity of polymyxin B nonapeptide

R. L. Danner, K. A. Joiner, M. Rubin, W. H. Patterson, N. Johnson, K. M. Ayers, J. E. Parillo

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Polymyxin B, a relatively toxic antibiotic, has potent endotoxin-neutralizing properties that may be beneficial as adjunctive therapy in gram-negative sepsis. Polymyxin B nonapeptide (deacylated polymyxin B) is devoid of antibiotic activity but retains the capacity to disorganize the outer membrane of gram-negative bacteria. To evaluate the potential therapeutic usefulness of this derivative, we produced purified polymyxin B nonapeptide, tested its in vivo toxicity in animals, and evaluated its in vitro antiendotoxin activity. Effectiveness as an antiendotoxin agent was assessed by examining the ability of polymyxin B nonapeptide to block the enhanced release of toxic oxygen radicals induced by lipopolysaccharide in human neutrophils (priming). In vivo, at doses of 1.5 and 3.0 mg/kg, polymyxin B nonapeptide did not exhibit the neuromuscular blocking, neurotoxic, or nephrotoxic effects that were observed with polymyxin B sulfate. Both polymyxin B and polymyxin B nonapeptide inhibited lipopolysaccharide-induced neutrophil priming in a concentration-dependent manner, but the parent compound, polymyxin B, was 63 times more effective on a weight basis. The inhibitory activity of both compounds, however, diminished rapidly when they were added after the start of the lipopolysaccharide-neutrophil incubation. We conclude that polymyxin B nonapeptide is less toxic that polymyxin B and, at the doses tested, lacks the neurotoxicity and nephrotoxicity of the parent compound. Polymyxin B nonapeptide retains the antiendotoxin activity of polymyxin B but is much less potent. The findings suggest that these compounds block an early step in the neutrophil priming process, possibly lipopolysaccharide attachment to or insertion into the neutrophil membrane.

Original languageEnglish (US)
Pages (from-to)1428-1434
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume33
Issue number9
DOIs
StatePublished - Jan 1 1989
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Danner, R. L., Joiner, K. A., Rubin, M., Patterson, W. H., Johnson, N., Ayers, K. M., & Parillo, J. E. (1989). Purification, toxicity, and antiendotoxin activity of polymyxin B nonapeptide. Antimicrobial Agents and Chemotherapy, 33(9), 1428-1434. https://doi.org/10.1128/AAC.33.9.1428