title: Bacterium-Derived Cell-Penetrating Peptides Deliver Gentamicin To Kill Intracellular Pathogens.
abstract: Commonly used antimicrobials show poor cellular uptake and often have limited access to intracellular targets, resulting in low antimicrobial activity against intracellular pathogens. An efficient delivery system to transport these drugs to the intracellular site of action is needed. Cell-penetrating peptides (CPPs) mediate the internalization of biologically active molecules into the cytoplasm. Here, we characterized two CPPs, α1H and α2H, derived from theYersinia enterocoliticaYopM effector protein. These CPPs, as well as Tat (trans-activator of transcription) from HIV-1, were used to deliver the antibiotic gentamicin to target intracellular bacteria. The YopM-derived CPPs penetrated different endothelial and epithelial cells to the same extent as Tat. CPPs were covalently conjugated to gentamicin, and CPP-gentamicin conjugates were used to target infected cells to kill multiple intracellular Gram-negative pathogenic bacteria, includingEscherichia coliK1,Salmonella entericaserovar Typhimurium, andShigella flexneriTaken together, CPPs show great potential as delivery vehicles for antimicrobial agents and may contribute to the generation of new therapeutic tools to treat infectious diseases caused by intracellular pathogens.
authors.affiliation: Institute of Infectiology, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Gomarasca
authors.affiliation: Institute of Infectiology, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany.
authors.forename: Thaynan
authors.initials: T
authors.lastname: F C Martins
authors.affiliation: Institute of Infectiology, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany.
authors.forename: Lilo
authors.initials: L
authors.lastname: Greune
authors.affiliation: College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, USA.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Hardwidge
authors.affiliation: Institute of Infectiology, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany.
authors.forename: M Alexander
authors.initials: MA
authors.lastname: Schmidt
authors.affiliation: Institute of Infectiology, Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Münster, Germany rueterc@uni-muenster.de.
authors.forename: Christian
authors.identifier: 0000-0003-1982-4811
authors.initials: C
authors.lastname: Rüter
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D004926:Escherichia coli / Q000187:drug effects; D005839:Gentamicins / Q000737:chemistry* / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D019779:Salmonella enterica / Q000187:drug effects; D012763:Shigella flexneri / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D057846:Cell-Penetrating Peptides; D005839:Gentamicins
keywords: CPP-translocated antimicrobials; antimicrobial drug delivery; cell-penetrating peptides; gentamicin; intracellular pathogenic bacteria