Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB)

Abstract

BackgroundCutaneous 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.Methodology/Principal FindingsHere 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.ConclusionsGiven 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.

Adverse health effects of humidifier disinfectants in Korea: lung toxicity of polyhexamethylene guanidine phosphate

“…Guanidine-based antimicrobials were thus believed to have low toxicity to humans (Ikeda et al, 1983(Ikeda et al, , 1984. However, recent accounts have reported PHMB penetrating mammalian cells and interacting with chromosomes, raising concerns about health hazards from guanidine-based antimicrobials (Allen et al, 2004(Allen et al, , 2006Chindera et al, 2016;Firdessa et al, 2015).…”

Bactericidal and Anti-biofilm Effects of Polyhexamethylene Biguanide in Models of Intracellular and Biofilm of Staphylococcus aureus Isolated from Bovine Mastitis

“…Antimicrobial polymers appear much less susceptible to acquired resistance, and they can be surprisingly effective against intracellular pathogens. For example, we recently reported that a cationic polymer, polyhexamethylene biguanide (PHMB) ( Figure 1 ), effectively killed intracellular S. aureus inside keratinocytes and the parasite Leishmania in macrophages, through a dynamin dependent uptake mechanism ( Firdessa et al, 2015 ; Kamaruzzaman et al, 2016 ). Therefore, we considered that PHMB might also be effective against intracellular S. aureus within bovine mammary epithelial cells.…”

Targeting the hard to reach: challenges and novel strategies in the treatment of intracellular bacterial infections

“…PHMB is able to enter a range of cell types, including many mammalian cells (Firdessa et al, , Chindera et al, ). Moreover, following mammalian cell entry, PHMB co‐localizes with intracellular MRSA inside the host cells (Kamaruzzaman et al, ).…”