Article ; Online: Antimicrobial peptide thanatin fused endolysin PA90 (Tha-PA90) for the control of Acinetobacter baumannii infection in mouse model.
2024 Volume 31, Issue 1, Page(s) 36
Abstract: Background: This study addresses the urgent need for infection control agents driven by the rise of drug-resistant pathogens such as Acinetobacter baumannii. Our primary aim was to develop and assess a novel endolysin, Tha-PA90, designed to combat these ...
| Abstract | Background: This study addresses the urgent need for infection control agents driven by the rise of drug-resistant pathogens such as Acinetobacter baumannii. Our primary aim was to develop and assess a novel endolysin, Tha-PA90, designed to combat these challenges. Methods: Tha-PA90 incorporates an antimicrobial peptide (AMP) called thanatin at its N-terminus, enhancing bacterial outer membrane permeability and reducing host immune responses. PA90 was selected as the endolysin component. The antibacterial activity of the purified Tha-PA90 was evaluated using an in vitro colony-forming unit (CFU) reduction assay and a membrane permeability test. A549 cells were utilized to measure the penetration into the cytosol and the cytotoxicity of Tha-PA90. Finally, infection control was monitored in A. baumannii infected mice following the intraperitoneal administration of Tha-PA90. Results: Tha-PA90 demonstrated remarkable in vitro efficacy, completely eradicating A. baumannii strains, even drug-resistant variants, at a low concentration of 0.5 μM. Notably, it outperformed thanatin, achieving only a < 3-log reduction at 4 μM. Tha-PA90 exhibited 2-3 times higher membrane permeability than a PA90 and thanatin mixture or PA90 alone. Tha-PA90 was found within A549 cells' cytosol with no discernible cytotoxic effects. Furthermore, Tha-PA90 administration extended the lifespan of A. baumannii-infected mice, reducing bacterial loads in major organs by up to 3 logs. Additionally, it decreased proinflammatory cytokine levels (TNF-α and IL-6), reducing the risk of sepsis from rapid bacterial lysis. Our findings indicate that Tha-PA90 is a promising solution for combating drug-resistant A. baumannii. Its enhanced efficacy, low cytotoxicity, and reduction of proinflammatory responses render it a potential candidate for infection control. Conclusions: This study underscores the significance of engineered endolysins in addressing the pressing challenge of drug-resistant pathogens and offers insights into improved infection management strategies. |
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| MeSH term(s) | Animals ; Mice ; Acinetobacter baumannii ; Antimicrobial Peptides ; Antimicrobial Cationic Peptides ; Anti-Bacterial Agents/pharmacology ; Acinetobacter Infections/drug therapy ; Microbial Sensitivity Tests ; Endopeptidases |
| Chemical Substances | thanatin ; endolysin (EC 3.4.99.-) ; Antimicrobial Peptides ; Antimicrobial Cationic Peptides ; Anti-Bacterial Agents ; Endopeptidases (EC 3.4.-) |
| Language | English |
| Publishing date | 2024-04-15 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 1193378-1 |
| ISSN | 1423-0127 ; 1021-7770 |
| ISSN (online) | 1423-0127 |
| ISSN | 1021-7770 |
| DOI | 10.1186/s12929-024-01027-4 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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