1887

Abstract

Broad-spectrum antimicrobials are needed to effectively treat patients infected in the event of a pandemic or intentional release of a pathogen prior to confirmation of the pathogen's identity. Engineered cationic antimicrobial peptides (eCAPs) display activity against a number of bacterial pathogens including multi-drug-resistant strains. Two lead eCAPs, WLBU2 and WR12, were compared with human cathelicidin (LL-37) against three highly pathogenic bacteria: Francisella tularensis, Yersinia pestis and Burkholderia pseudomallei. Both WLBU2 and WR12 demonstrated bactericidal activity greater than that of LL-37, particularly against F. tularensis and Y. pestis. Only WLBU2 had bactericidal activity against B. pseudomallei. WLBU2, WR12 and LL-37 were all able to inhibit the growth of the three bacteria in vitro. Because these bacteria can be facultative intracellular pathogens, preferentially infecting macrophages and dendritic cells, we evaluated the activity of WLBU2 against F. tularensis in an ex vivo infection model with J774 cells, a mouse macrophage cell line. In that model WLBU2 was able to achieve greater than 50 % killing of F. tularensis at a concentration of 12.5 μM. These data show the therapeutic potential of eCAPs, particularly WLBU2, as a broad-spectrum antimicrobial for treating highly pathogenic bacterial infections.

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2016-02-01
2019-10-20
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References

  1. Boman H. G.. ( 1995;). Peptide antibiotics and their role in innate immunity. Annu Rev Immunol 13: 61–92 [CrossRef] [PubMed].
    [Google Scholar]
  2. Brogden K. A.. ( 2005;). Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?. Nat Rev Microbiol 3: 238–250 [CrossRef] [PubMed].
    [Google Scholar]
  3. Burtnick M. N., Woods D. E.. ( 1999;). Isolation of polymyxin B-susceptible mutants of Burkholderia pseudomallei and molecular characterization of genetic loci involved in polymyxin B resistance. Antimicrob Agents Chemother 43: 2648–2656.
    [Google Scholar]
  4. Chantratita N., Wuthiekanun V., Boonbumrung K., Tiyawisutsri R., Vesaratchavest M., Limmathurotsakul D., Chierakul W., Wongratanacheewin S., Pukritiyakamee S., other authors. ( 2007;). Biological relevance of colony morphology and phenotypic switching by Burkholderia pseudomallei. J Bacteriol 189: 807–817 [CrossRef] [PubMed].
    [Google Scholar]
  5. Deslouches B., Islam K., Craigo J. K., Paranjape S. M., Montelaro R. C., Mietzner T. A.. ( 2005a;). Activity of the de novo engineered antimicrobial peptide WLBU2 against Pseudomonas aeruginosa in human serum and whole blood: implications for systemic applications. Antimicrob Agents Chemother 49: 3208–3216 [CrossRef] [PubMed].
    [Google Scholar]
  6. Deslouches B., Phadke S. M., Lazarevic V., Cascio M., Islam K., Montelaro R. C., Mietzner T. A.. ( 2005b;). De novo generation of cationic antimicrobial peptides: influence of length and tryptophan substitution on antimicrobial activity. Antimicrob Agents Chemother 49: 316–322 [CrossRef] [PubMed].
    [Google Scholar]
  7. Faith S. A., Smith L. P., Swatland A. S., Reed D. S.. ( 2012;). Growth conditions and environmental factors impact aerosolization but not virulence of Francisella tularensis infection in mice. Front Cell Infect Microbiol 2: 126.[CrossRef]
    [Google Scholar]
  8. Galván E. M., Lasaro M. A., Schifferli D. M.. ( 2008;). Capsular antigen fraction 1 and Pla modulate the susceptibility of Yersinia pestis to pulmonary antimicrobial peptides such as cathelicidin. Infect Immun 76: 1456–1464 [CrossRef] [PubMed].
    [Google Scholar]
  9. Goldman M. J., Anderson G. M., Stolzenberg E. D., Kari U. P., Zasloff M., Wilson J. M.. ( 1997;). Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88: 553–560 [CrossRef] [PubMed].
    [Google Scholar]
  10. Hancock R. E., Chapple D. S.. ( 1999;). Peptide antibiotics. Antimicrob Agents Chemother 43: 1317–1323.
    [Google Scholar]
  11. Hayden H. S., Lim R., Brittnacher M. J., Sims E. H., Ramage E. R., Fong C., Wu Z., Crist E., Chang J., other authors. ( 2012;). Evolution of Burkholderia pseudomallei in recurrent melioidosis. PLoS One 7: e36507 [CrossRef] [PubMed].
    [Google Scholar]
  12. Hazlett K. R., Caldon S. D., McArthur D. G., Cirillo K. A., Kirimanjeswara G. S., Magguilli M. L., Malik M., Shah A., Broderick S., other authors. ( 2008;). Adaptation of Francisella tularensis to the mammalian environment is governed by cues which can be mimicked in vitro. Infect Immun 76: 4479–4488 [CrossRef] [PubMed].
    [Google Scholar]
  13. Kanthawong S., Nazmi K., Wongratanacheewin S., Bolscher J. G., Wuthiekanun V., Taweechaisupapong S.. ( 2009;). In vitro susceptibility of Burkholderia pseudomallei to antimicrobial peptides. Int J Antimicrob Agents 34: 309–314 [CrossRef] [PubMed].
    [Google Scholar]
  14. Kanthawong S., Bolscher J. G., Veerman E. C., van Marle J., de Soet H. J., Nazmi K., Wongratanacheewin S., Taweechaisupapong S.. ( 2012;). Antimicrobial and antibiofilm activity of LL-37 and its truncated variants against Burkholderia pseudomallei. Int J Antimicrob Agents 39: 39–44 [CrossRef] [PubMed].
    [Google Scholar]
  15. Leelarasamee A.. ( 1998;). Burkholderia pseudomallei: the unbeatable foe?. Southeast Asian J Trop Med Public Health 29: 410–415.
    [Google Scholar]
  16. Madhongsa K., Pasan S., Phophetleb O., Nasompag S., Thammasirirak S., Daduang S., Taweechaisupapong S., Lomize A. L., Patramanon R.. ( 2013;). Antimicrobial action of the cyclic peptide bactenecin on Burkholderia pseudomallei correlates with efficient membrane permeabilization. PLoS Negl Trop Dis 7: e2267 [CrossRef] [PubMed].
    [Google Scholar]
  17. Miller M. A., Cloyd M. W., Liebmann J., Rinaldo C. R. Jr., Islam K. R., Wang S. Z., Mietzner T. A., Montelaro R. C.. ( 1993;). Alterations in cell membrane permeability by the lentivirus lytic peptide (LLP-1) of HIV-1 transmembrane protein. Virology 196: 89–100 [CrossRef] [PubMed].
    [Google Scholar]
  18. Ntwasa M.. ( 2012;). Cationic peptide interactions with biological macromolecules. . In Binding Proteins, pp. 139–160. Edited by Abdelmohsen K.. Rijeka: InTech;.
    [Google Scholar]
  19. Reckseidler-Zenteno S. L., DeVinney R., Woods D. E.. ( 2005;). The capsular polysaccharide of Burkholderia pseudomallei contributes to survival in serum by reducing complement factor C3b deposition. Infect Immun 73: 1106–1115 [CrossRef] [PubMed].
    [Google Scholar]
  20. Steiner D. J., Furuya Y., Metzger D. W.. ( 2014;). Host-pathogen interactions and immune evasion strategies in Francisella tularensis pathogenicity. Infect Drug Resist 7: 239–251.
    [Google Scholar]
  21. Tencza S. B., Creighton D. J., Yuan T., Vogel H. J., Montelaro R. C., Mietzner T. A.. ( 1999;). Lentivirus-derived antimicrobial peptides: increased potency by sequence engineering and dimerization. J Antimicrob Chemother 44: 33–41 [CrossRef] [PubMed].
    [Google Scholar]
  22. Vonkavaara M., Pavel S. T., Hölzl K., Nordfelth R., Sjöstedt A., Stöven S.. ( 2013;). Francisella is sensitive to insect antimicrobial peptides. J Innate Immun 5: 50–59 [CrossRef] [PubMed].
    [Google Scholar]
  23. Wikraiphat C., Charoensap J., Utaisincharoen P., Wongratanacheewin S., Taweechaisupapong S., Woods D. E., Bolscher J. G., Sirisinha S.. ( 2009;). Comparative in vivo and in vitro analyses of putative virulence factors of Burkholderia pseudomallei using lipopolysaccharide, capsule and flagellin mutants. FEMS Immunol Med Microbiol 56: 253–259 [CrossRef] [PubMed].
    [Google Scholar]
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