Efficacy of Artilysin Art-175 against Resistant and Persistent Acinetobacter baumannii

• Published in: Antimicrobial agents and chemotherapy Vol. 60; no. 6; pp. 3480 - 3488
• Main Authors: Defraine, Valerie, Schuermans, Joris, Grymonprez, Barbara, Govers, Sander K., Aertsen, Abram, Fauvart, Maarten, Michiels, Jan, Lavigne, Rob, Briers, Yves
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.06.2016
• Subjects: Acinetobacter baumannii; Acinetobacter baumannii - drug effects; Acinetobacter Infections; Acinetobacter Infections - drug therapy; Acinetobacter Infections - microbiology; Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacology; Cathelicidins; Cathelicidins - pharmacology; Drug Resistance, Multiple, Bacterial; Edetic Acid - pharmacology; Endopeptidases; Endopeptidases - chemistry; Endopeptidases - pharmacology; Experimental Therapeutics; Humans; Microbial Sensitivity Tests; Microfluidic Analytical Techniques; Pseudomonadales; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Recombinant Fusion Proteins; Recombinant Fusion Proteins - pharmacology
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00285-16

Bacteriophage-encoded endolysins have shown promise as a novel class of antibacterials with a unique mode of action, i.e., peptidoglycan degradation. However, Gram-negative pathogens are generally not susceptible due to their protective outer membrane. Artilysins overcome this barrier. Artilysins are optimized, engineered fusions of selected endolysins with specific outer membrane-destabilizing peptides. Artilysin Art-175 comprises a modified variant of endolysin KZ144 with an N-terminal fusion to SMAP-29. Previously, we have shown the high susceptibility of Pseudomonas aeruginosa to Art-175. Here, we report that Art-175 is highly bactericidal against stationary-phase cells of multidrug-resistant Acinetobacter baumannii , even resulting in a complete elimination of large inocula (≥10 8 CFU/ml). Besides actively dividing cells, Art-175 also kills persisters. Instantaneous killing of A. baumannii upon contact with Art-175 could be visualized after immobilization of the bacteria in a microfluidic flow cell. Effective killing of a cell takes place through osmotic lysis after peptidoglycan degradation. The killing rate is enhanced by the addition of 0.5 mM EDTA. No development of resistance to Art-175 under selection pressure and no cross-resistance with existing resistance mechanisms could be observed. In conclusion, Art-175 represents a highly active Artilysin against both A. baumannii and P. aeruginosa , two of the most life-threatening pathogens of the order Pseudomonadales .