title: Cell entry and antimicrobial properties of eukaryotic cell-penetrating peptides.
abstract: Antimicrobial drug action is limited by both microbial and host cell membranes. Microbes stringently exclude the entry of most drugs, and mammalian membranes limit drug distribution and access to intracellular pathogens. Recently, cell-penetrating peptides (CPPs) have been developed as carriers to improve mammalian cell uptake. Given that CPPs are cationic and often amphipathic, similar to membrane active antimicrobial peptides, it may be possible to use CPP activity to improve drug delivery to microbes. Here, two CPPs, TP10 and pVEC, were found to enter a range of bacteria and fungi. The uptake route involves rapid surface accumulation within minutes followed by cell entry. TP10 inhibited Candida albicans and Staphylococcus aureus growth, and pVEC inhibited Mycobacterium smegmatis growth at low micromolar doses, below the levels that harmed human HeLa cells. Therefore, although TP10 and pVEC entered all cell types tested, they preferentially damage microbes, and this effect was sufficient to clear HeLa cell cultures from noninvasive S. aureus infection. Also, conversion of the cytotoxicity indicator dye SYTOX Green showed that TP10 causes rapid and lethal permeabilization of S. aureus and pVEC permeabilizes M. smegmatis, but not HeLa cells. Therefore, TP10 and pVEC can enter both mammalian and microbial cells and preferentially permeabilize and kill microbes.
authors.affiliation: Center for Genomics and Bioinformatics, Karolinska Institutet, Berzelius väg 35, 17177 Stockholm, Sweden.
authors.forename: Natalia
authors.initials: N
authors.lastname: Nekhotiaeva
authors.forename: Anna
authors.initials: A
authors.lastname: Elmquist
authors.forename: Gunaratna Kuttuva
authors.initials: GK
authors.lastname: Rajarao
authors.forename: Mattias
authors.initials: M
authors.lastname: Hällbrink
authors.forename: Ulo
authors.initials: U
authors.lastname: Langel
authors.forename: Liam
authors.initials: L
authors.lastname: Good
mesh_terms: D000890:Anti-Infective Agents / Q000378:metabolism* / Q000494:pharmacology; D001419:Bacteria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability; D002477:Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005658:Fungi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D013045:Species Specificity
chemical_list: D000890:Anti-Infective Agents; D010455:Peptides; C437783:pVEC peptide