title: Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB).
abstract: BACKGROUND
  Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed.
  
  
  RESULTS
  Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB.
  
  
  CONCLUSIONS
  Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators.
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Rebuma
authors.initials: R
authors.lastname: Firdessa
authors.affiliation: Royal Veterinary College, University of London, London, United Kingdom.
authors.forename: Liam
authors.initials: L
authors.lastname: Good
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany.
authors.forename: Maria Cecilia
authors.initials: MC
authors.lastname: Amstalden
authors.affiliation: Royal Veterinary College, University of London, London, United Kingdom.
authors.forename: Kantaraja
authors.initials: K
authors.lastname: Chindera
authors.affiliation: Royal Veterinary College, University of London, London, United Kingdom.
authors.forename: Nor Fadhilah
authors.initials: NF
authors.lastname: Kamaruzzaman
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Schultheis
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Röger
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Hecht
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Oelschlaeger
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Meinel
authors.affiliation: Institute for Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany.
authors.forename: Tessa
authors.initials: T
authors.lastname: Lühmann
authors.affiliation: Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Moll
mesh_terms: D000818:Animals; D001645:Biguanides / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D018320:Leishmania major / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology
chemical_list: D001645:Biguanides; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C031233:polihexanide