In Vitro Antibacterial Properties of Pexiganan, an Analog of Magainin

ABSTRACT Pexiganan, a 22-amino-acid antimicrobial peptide, is an analog of the magainin peptides isolated from the skin of the African clawed frog. Pexiganan exhibited in vitro broad-spectrum antibacterial activity when it was tested against 3,109 clinical isolates of gram-positive and gram-negative, anaerobic and aerobic bacteria. The pexiganan MIC at which 90% of isolates are inhibited (MIC90) was 32 μg/ml or less forStaphylococcus spp., Streptococcus spp.,Enterococcus faecium, Corynebacterium spp.,Pseudomonas spp., Acinetobacter spp.,Stenotrophomonas spp., certain species of the familyEnterobacteriaceae, Bacteroides spp.,Peptostreptococcus spp., and Propionibacteriumspp. Comparison of the MICs and minimum bactericidal concentrations (MBCs) of pexiganan for 143 isolates representing 32 species demonstrated that for 92% of the isolates tested, MBCs were the same or within 1 twofold difference of the MICs, consistent with a bactericidal mechanism of action. Killing curve analysis showed that pexiganan killed Pseudomonas aeruginosa rapidly, with 106 organisms/ml eliminated within 20 min of treatment with 16 μg of pexiganan per ml. No evidence of cross-resistance to a number of other antibiotic classes was observed, as determined by the equivalence of the MIC50s and the MIC90s of pexiganan for strains resistant to oxacillin, cefazolin, cefoxitin, imipenem, ofloxacin, ciprofloxacin, gentamicin, and clindamicin versus those for strains susceptible to these antimicrobial agents. Attempts to generate resistance in several bacterial species through repeated passage with subinhibitory concentrations of pexiganan were unsuccessful. In conclusion, pexiganan exhibits properties in vitro which make it an attractive candidate for development as a topical antimicrobial agent.

[1]  M. Zasloff,et al.  Potential therapeutic applications of magainins and other antimicrobial agents of animal origin. , 2007, Ciba Foundation symposium.

[2]  Steven D. Brown,et al.  In Vitro Antimicrobial Activity of MSI-78, a Magainin Analog , 1998, Antimicrobial Agents and Chemotherapy.

[3]  S. Miller,et al.  PmrA–PmrB‐regulated genes necessary for 4‐aminoarabinose lipid A modification and polymyxin resistance , 1998, Molecular microbiology.

[4]  M. Wenk,et al.  Magainin 2 amide interaction with lipid membranes: calorimetric detection of peptide binding and pore formation. , 1998, Biochemistry.

[5]  M. Ackermann,et al.  Epithelial antibiotic induced in states of disease. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[6]  J. Fiddes,et al.  Protegrin-1: a broad-spectrum, rapidly microbicidal peptide with in vivo activity , 1997, Antimicrobial agents and chemotherapy.

[7]  N. Takahashi,et al.  On the antibacterial activity of normal and reversed magainin 2 analogs against Helicobacter pylori. , 1997, Biological & pharmaceutical bulletin.

[8]  Benjamin A Lipsky,et al.  Microbial eradication and clinical resolution of infected diabetic foot ulcers treated with topical MSI-78 vs oral ofloxacin , 1997 .

[9]  I. Nes,et al.  Ribosomally synthesized antimicrobial peptides: their function, structure, biogenesis, and mechanism of action , 1997, Archives of Microbiology.

[10]  R. Hancock,et al.  Peptide antibiotics , 1997, The Lancet.

[11]  S J Ludtke,et al.  Membrane pores induced by magainin. , 1996, Biochemistry.

[12]  B. Schonwetter,et al.  Epithelial antibiotics induced at sites of inflammation. , 1995, Science.

[13]  G M Anantharamaiah,et al.  Molecular basis for prokaryotic specificity of magainin-induced lysis. , 1995, Biochemistry.

[14]  E. Groisman,et al.  How bacteria resist killing by host-defense peptides. , 1994, Trends in microbiology.

[15]  I. Shalit,et al.  All‐D‐magainin: chirality, antimicrobial activity and proteolytic resistance , 1990, FEBS letters.

[16]  R. B. Merrifield,et al.  All-D amino acid-containing channel-forming antibiotic peptides. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Zasloff,et al.  Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[18]  L. Reimer,et al.  Antibiotics in laboratory medicine , 1987 .

[19]  S. Fesik,et al.  Decreased binding of antibiotics to lipopolysaccharides from polymyxin-resistant strains of Escherichia coli and Salmonella typhimurium , 1987, Antimicrobial Agents and Chemotherapy.

[20]  E. Bruck,et al.  National Committee for Clinical Laboratory Standards. , 1980, Pediatrics.

[21]  Mary Jane Ferraro,et al.  Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically : approved standard , 2000 .

[22]  E. Groisman,et al.  The genetic basis of microbial resistance to antimicrobial peptides. , 1997, Methods in molecular biology.

[23]  A. Mor,et al.  Peptides as weapons against microorganisms in the chemical defense system of vertebrates. , 1995, Annual review of microbiology.

[24]  H. G. Boman,et al.  Peptide antibiotics and their role in innate immunity. , 1995, Annual review of immunology.

[25]  J. Waitz.  Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically , 1990 .