title: Art-175 is a highly efficient antibacterial against multidrug-resistant strains and persisters of Pseudomonas aeruginosa.
abstract: Artilysins constitute a novel class of efficient enzyme-based antibacterials. Specifically, they covalently combine a bacteriophage-encoded endolysin, which degrades the peptidoglycan, with a targeting peptide that transports the endolysin through the outer membrane of Gram-negative bacteria. Art-085, as well as Art-175, its optimized homolog with increased thermostability, are each composed of the sheep myeloid 29-amino acid (SMAP-29) peptide fused to the KZ144 endolysin. In contrast to KZ144, Art-085 and Art-175 pass the outer membrane and kill Pseudomonas aeruginosa, including multidrug-resistant strains, in a rapid and efficient (∼ 5 log units) manner. Time-lapse microscopy confirms that Art-175 punctures the peptidoglycan layer within 1 min, inducing a bulging membrane and complete lysis. Art-175 is highly refractory to resistance development by naturally occurring mutations. In addition, the resistance mechanisms against 21 therapeutically used antibiotics do not show cross-resistance to Art-175. Since Art-175 does not require an active metabolism for its activity, it has a superior bactericidal effect against P. aeruginosa persisters (up to >4 log units compared to that of the untreated controls). In summary, Art-175 is a novel antibacterial that is well suited for a broad range of applications in hygiene and veterinary and human medicine, with a unique potential to target persister-driven chronic infections.
authors.affiliation: Laboratory of Gene Technology, Department Biosystems, KU Leuven, Heverlee, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Briers
authors.affiliation: Laboratory of Gene Technology, Department Biosystems, KU Leuven, Heverlee, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Walmagh
authors.affiliation: Laboratory of Gene Technology, Department Biosystems, KU Leuven, Heverlee, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Grymonprez
authors.affiliation: Lisando GmbH, Regensburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Biebl
authors.affiliation: Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, Belgium.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pirnay
authors.affiliation: Centre of Microbial and Plant Genetics, Department Microbial and Molecular Systems, KU Leuven, Heverlee, Belgium.
authors.forename: Valerie
authors.initials: V
authors.lastname: Defraine
authors.affiliation: Centre of Microbial and Plant Genetics, Department Microbial and Molecular Systems, KU Leuven, Heverlee, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Michiels
authors.affiliation: Laboratory of Food Microbiology, Department of Microbial and Molecular Systems, KU Leuven, Heverlee, Belgium.
authors.forename: William
authors.initials: W
authors.lastname: Cenens
authors.affiliation: Laboratory of Food Microbiology, Department of Microbial and Molecular Systems, KU Leuven, Heverlee, Belgium.
authors.forename: Abram
authors.initials: A
authors.lastname: Aertsen
authors.affiliation: Lisando GmbH, Regensburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Miller
authors.affiliation: Laboratory of Gene Technology, Department Biosystems, KU Leuven, Heverlee, Belgium rob.lavigne@kuleuven.be.
authors.forename: Rob
authors.initials: R
authors.lastname: Lavigne
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D054804:Cathelicidins / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003001:Cloning, Molecular; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects* / Q000235:genetics; D010450:Endopeptidases / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D010457:Peptidoglycan / Q000378:metabolism; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D054804:Cathelicidins; D010457:Peptidoglycan; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D010450:Endopeptidases; C000601046:Art-175
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