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Antimicrob Agents Chemother. 2014 Jul;58(7):3774-84. doi: 10.1128/AAC.02668-14. Epub 2014 Apr 21.

Art-175 is a highly efficient antibacterial against multidrug-resistant strains and persisters of Pseudomonas aeruginosa.

Author information

1
Laboratory of Gene Technology, Department Biosystems, KU Leuven, Heverlee, Belgium.
2
Lisando GmbH, Regensburg, Germany.
3
Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, Brussels, Belgium.
4
Centre of Microbial and Plant Genetics, Department Microbial and Molecular Systems, KU Leuven, Heverlee, Belgium.
5
Laboratory of Food Microbiology, Department of Microbial and Molecular Systems, KU Leuven, Heverlee, Belgium.
6
Laboratory of Gene Technology, Department Biosystems, KU Leuven, Heverlee, Belgium rob.lavigne@kuleuven.be.

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.

PMID:
24752267
PMCID:
PMC4068523
DOI:
10.1128/AAC.02668-14
[Indexed for MEDLINE]
Free PMC Article

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