Antimicrobial peptide thanatin fused endolysin PA90 (Tha-PA90) for the control of Acinetobacter baumannii infection in mouse model
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 incorpora...
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| Format: | Article |
| Language: | English |
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BMC
2024-04-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | https://doi.org/10.1186/s12929-024-01027-4 |
| _version_ | 1797199254273392640 |
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| author | Jeonghyun Lim Heejoon Myung Daejin Lim Miryoung Song |
| author_facet | Jeonghyun Lim Heejoon Myung Daejin Lim Miryoung Song |
| author_sort | Jeonghyun Lim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T07:12:50Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-04-24T07:12:50Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-50cd1be86cea4a1aa30dd5cc0f769bd62024-04-21T11:26:14ZengBMCJournal of Biomedical Science1423-01272024-04-013111910.1186/s12929-024-01027-4Antimicrobial peptide thanatin fused endolysin PA90 (Tha-PA90) for the control of Acinetobacter baumannii infection in mouse modelJeonghyun Lim0Heejoon Myung1Daejin Lim2Miryoung Song3Department of Bioscience and Biotechnology, Hankuk University of Foreign StudiesDepartment of Bioscience and Biotechnology, Hankuk University of Foreign StudiesDivision of Biomedical Convergence, College of Biomedical Science, Kangwon National UniversityDepartment of Bioscience and Biotechnology, Hankuk University of Foreign StudiesAbstract 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.https://doi.org/10.1186/s12929-024-01027-4EndolysinThanatinTha-PA90Designed endolysinA. baumannii infectionDrug-resistant gram-negative pathogen |
| spellingShingle | Jeonghyun Lim Heejoon Myung Daejin Lim Miryoung Song Antimicrobial peptide thanatin fused endolysin PA90 (Tha-PA90) for the control of Acinetobacter baumannii infection in mouse model Journal of Biomedical Science Endolysin Thanatin Tha-PA90 Designed endolysin A. baumannii infection Drug-resistant gram-negative pathogen |
| title | Antimicrobial peptide thanatin fused endolysin PA90 (Tha-PA90) for the control of Acinetobacter baumannii infection in mouse model |
| title_full | Antimicrobial peptide thanatin fused endolysin PA90 (Tha-PA90) for the control of Acinetobacter baumannii infection in mouse model |
| title_fullStr | Antimicrobial peptide thanatin fused endolysin PA90 (Tha-PA90) for the control of Acinetobacter baumannii infection in mouse model |
| title_full_unstemmed | Antimicrobial peptide thanatin fused endolysin PA90 (Tha-PA90) for the control of Acinetobacter baumannii infection in mouse model |
| title_short | Antimicrobial peptide thanatin fused endolysin PA90 (Tha-PA90) for the control of Acinetobacter baumannii infection in mouse model |
| title_sort | antimicrobial peptide thanatin fused endolysin pa90 tha pa90 for the control of acinetobacter baumannii infection in mouse model |
| topic | Endolysin Thanatin Tha-PA90 Designed endolysin A. baumannii infection Drug-resistant gram-negative pathogen |
| url | https://doi.org/10.1186/s12929-024-01027-4 |
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