Antimicrobial Agents and Chemotherapy vol:58 issue:7 pages:3774-3784
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 transfers 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 comprised of the 29 amino acid SMAP-29 peptide fused to 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) manner. Time-lapse microscopy confirms that Art-175 punctures the peptidoglycan layer within a minute, 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 more than 4 log). In summary, Art-175 is a novel antibacterial well suited for a broad range of applications in hygiene, veterinary and human medicine, with the unique potential to target persister-driven chronic infections.