title: The antimicrobial polymer PHMB enters cells and selectively condenses bacterial chromosomes.
abstract: To combat infection and antimicrobial resistance, it is helpful to elucidate drug mechanism(s) of action. Here we examined how the widely used antimicrobial polyhexamethylene biguanide (PHMB) kills bacteria selectively over host cells. Contrary to the accepted model of microbial membrane disruption by PHMB, we observed cell entry into a range of bacterial species, and treated bacteria displayed cell division arrest and chromosome condensation, suggesting DNA binding as an alternative antimicrobial mechanism. A DNA-level mechanism was confirmed by observations that PHMB formed nanoparticles when mixed with isolated bacterial chromosomal DNA and its effects on growth were suppressed by pairwise combination with the DNA binding ligand Hoechst 33258. PHMB also entered mammalian cells, but was trapped within endosomes and excluded from nuclei. Therefore, PHMB displays differential access to bacterial and mammalian cellular DNA and selectively binds and condenses bacterial chromosomes. Because acquired resistance to PHMB has not been reported, selective chromosome condensation provides an unanticipated paradigm for antimicrobial action that may not succumb to resistance.
authors.affiliation: Department of Pathology and Pathogen Biology, Royal Veterinary College, University of London, Royal College Street, London, NW1 0TU, UK.|Tecrea Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London, NW1 0NH, UK.
authors.forename: Kantaraja
authors.initials: K
authors.lastname: Chindera
authors.affiliation: Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi-110 007, India.
authors.forename: Manohar
authors.initials: M
authors.lastname: Mahato
authors.affiliation: Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Mall Road, Delhi-110 007, India.
authors.forename: Ashwani Kumar
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Centre for Clinical Science &Technology, University College London, Wolfson House, 2-10 Stephenson Way, London NW1 2HE, UK.
authors.forename: Harry
authors.initials: H
authors.lastname: Horsley
authors.affiliation: Tecrea Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London, NW1 0NH, UK.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Kloc-Muniak
authors.affiliation: Department of Pathology and Pathogen Biology, Royal Veterinary College, University of London, Royal College Street, London, NW1 0TU, UK.|Faculty of Veterinary Medicine, Universiti Malaysia Kelantan, Locked bag 36, Pengkalan Chepa, 16100 Kota Bharu, Kelantan, Malaysia.
authors.forename: Nor Fadhilah
authors.initials: NF
authors.lastname: Kamaruzzaman
authors.affiliation: Division of Animal Biotechnology, Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh, 243 122, India.
authors.forename: Satish
authors.initials: S
authors.lastname: Kumar
authors.affiliation: School of Biology, University of Newcastle, Newcastle upon Tyne, NE1 7RU, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: McFarlane
authors.affiliation: School of Biology, University of Newcastle, Newcastle upon Tyne, NE1 7RU, UK.
authors.forename: Jem
authors.initials: J
authors.lastname: Stach
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3C, 2200 Copenhagen N, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bentin
authors.affiliation: Department of Pathology and Pathogen Biology, Royal Veterinary College, University of London, Royal College Street, London, NW1 0TU, UK.|Tecrea Ltd, London Bioscience Innovation Centre, 2 Royal College Street, London, NW1 0NH, UK.
authors.forename: Liam
authors.initials: L
authors.lastname: Good
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001410:Bacillus megaterium / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D001645:Biguanides / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects; D022004:Chromosome Structures / Q000187:drug effects; D002876:Chromosomes, Bacterial / Q000235:genetics*; D006224:Cricetinae; D003412:Cricetulus; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006736:Horses; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001645:Biguanides; C031233:polihexanide