Art-175 Is a Highly Efficient Antibacterial against Multidrug-Resistant Strains and Persisters of Pseudomonas aeruginosa

• Published in: Antimicrobial agents and chemotherapy Vol. 58; no. 7; pp. 3774 - 3784
• Main Authors: Briers, Yves, Walmagh, Maarten, Grymonprez, Barbara, Biebl, Manfred, Pirnay, Jean-Paul, Defraine, Valerie, Michiels, Jan, Cenens, William, Aertsen, Abram, Miller, Stefan, Lavigne, Rob
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for Microbiology 01.07.2014
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Cathelicidins; Cathelicidins - pharmacology; Cell Survival - drug effects; Cloning, Molecular; Drug Resistance, Multiple, Bacterial; Drug Resistance, Multiple, Bacterial - drug effects; Drug Resistance, Multiple, Bacterial - genetics; Endopeptidases; Endopeptidases - pharmacology; Experimental Therapeutics; Humans; Medical sciences; Mice; Microbial Sensitivity Tests; Peptidoglycan - metabolism; Pharmacology. Drug treatments; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - genetics; Pseudomonas Infections - microbiology; Recombinant Fusion Proteins; Recombinant Fusion Proteins - pharmacology; Recombinant Proteins - chemistry; Pseudomonadales; Persistent infection; Multiple resistance; Bacteria; Pseudomonadaceae; Pseudomonas aeruginosa; Antibacterial agent; Mechanism of action; Strain
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/AAC.02668-14

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.