Chimeric bacteriocin S5-PmnH engineered by domain swapping efficiently controls Pseudomonas aeruginosa infection in murine keratitis and lung models

• Published in: Scientific reports 2022-04, Vol.12 (1), p.5865-5865, Article 5865
• Main Authors: Paškevičius, Šarūnas, Dapkutė, Viktorija, Misiūnas, Audrius, Balzaris, Modestas, Thommes, Pia, Sattar, Abdul, Gleba, Yuri, Ražanskienė, Aušra
• Format: Article
• Language: English
• Subjects: 631/154; 631/326; 631/337; 631/61; Animal models; Animals; Anti-Bacterial Agents - pharmacology; Anti-Infective Agents - metabolism; Antimicrobial agents; Bacteria; Bacteriocins; Bacteriocins - genetics; Bacteriocins - metabolism; Bacteriocins - pharmacology; Bronchopulmonary infection; Chimera - metabolism; Genomes; Gram-negative bacteria; Humanities and Social Sciences; Infections; Keratitis; Keratitis - drug therapy; Lung - metabolism; Mice; multidisciplinary; Multidrug resistance; Phylogeny; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - metabolism; Pseudomonas Infections - drug therapy; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-09865-8

Rampant rise of multidrug resistant strains among Gram-negative bacteria has necessitated investigation of alternative antimicrobial agents with novel modes of action including antimicrobial proteins such as bacteriocins. The main hurdle in the clinical development of bacteriocin biologics is their narrow specificity and limited strain activity spectrum. Genome mining of bacteria for broadly active bacteriocins have identified a number of promising candidates but attempts to improve these natural multidomain proteins further, for example by combining domains of different origin, have so far met with limited success. We have found that domain swapping of Pseudomonas bacteriocins of porin type, when carried out between phylogenetically related molecules with similar mechanism of activity, allows the generation of highly active molecules with broader spectrum of activity, for example by abolishing strain resistance due to the presence of immunity proteins. The most broadly active chimera engineered in this study, S5-PmnH, exhibits excellent control of Pseudomonas aeruginosa infection in validated murine keratitis and lung infection models.