Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection
Carbapenem-resistant <i>A. baumannii</i> (CRAB) infection can cause acute host reactions that lead to high-fatality sepsis, making it important to develop new therapeutic options. Previously, we developed a short 9-meric peptide, Pro9-3D, with significant antibacterial and cytotoxic effe...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/22/12520 |
| _version_ | 1797509898192289792 |
|---|---|
| author | Manigandan Krishnan Joonhyeok Choi Ahjin Jang Young Kyung Yoon Yangmee Kim |
| author_facet | Manigandan Krishnan Joonhyeok Choi Ahjin Jang Young Kyung Yoon Yangmee Kim |
| author_sort | Manigandan Krishnan |
| collection | DOAJ |
| description | Carbapenem-resistant <i>A. baumannii</i> (CRAB) infection can cause acute host reactions that lead to high-fatality sepsis, making it important to develop new therapeutic options. Previously, we developed a short 9-meric peptide, Pro9-3D, with significant antibacterial and cytotoxic effects. In this study, we attempted to produce safer peptide antibiotics against CRAB by reversing the parent sequence to generate R-Pro9-3 and R-Pro9-3D. Among the tested peptides, R-Pro9-3D had the most rapid and effective antibacterial activity against Gram-negative bacteria, particularly clinical CRAB isolates. Analyses of antimicrobial mechanisms based on lipopolysaccharide (LPS)-neutralization, LPS binding, and membrane depolarization, as well as SEM ultrastructural investigations, revealed that R-Pro9-3D binds strongly to LPS and impairs the membrane integrity of CRAB by effectively permeabilizing its outer membrane. R-Pro9-3D was also less cytotoxic and had better proteolytic stability than Pro9-3D and killed biofilm forming CRAB. As an LPS-neutralizing peptide, R-Pro9-3D effectively reduced LPS-induced pro-inflammatory cytokine levels in RAW 264.7 cells. The antiseptic abilities of R-Pro9-3D were also investigated using a mouse model of CRAB-induced sepsis, which revealed that R-Pro9-3D reduced multiple organ damage and attenuated systemic infection by acting as an antibacterial and immunosuppressive agent. Thus, R-Pro9-3D displays potential as a novel antiseptic peptide for treating Gram-negative CRAB infections. |
| first_indexed | 2024-03-10T05:25:13Z |
| format | Article |
| id | doaj.art-0156f4d1ee5d413193f484763957c9a9 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T05:25:13Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0156f4d1ee5d413193f484763957c9a92023-11-22T23:43:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122221252010.3390/ijms222212520Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant <i>Acinetobacter baumannii</i> InfectionManigandan Krishnan0Joonhyeok Choi1Ahjin Jang2Young Kyung Yoon3Yangmee Kim4Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, KoreaDepartment of Bioscience and Biotechnology, Konkuk University, Seoul 05029, KoreaDepartment of Bioscience and Biotechnology, Konkuk University, Seoul 05029, KoreaDepartment of Internal Medicine, Division of Infectious Diseases, College of Medicine, Korea University Anam Hospital, Korea University, Seoul 02841, KoreaDepartment of Bioscience and Biotechnology, Konkuk University, Seoul 05029, KoreaCarbapenem-resistant <i>A. baumannii</i> (CRAB) infection can cause acute host reactions that lead to high-fatality sepsis, making it important to develop new therapeutic options. Previously, we developed a short 9-meric peptide, Pro9-3D, with significant antibacterial and cytotoxic effects. In this study, we attempted to produce safer peptide antibiotics against CRAB by reversing the parent sequence to generate R-Pro9-3 and R-Pro9-3D. Among the tested peptides, R-Pro9-3D had the most rapid and effective antibacterial activity against Gram-negative bacteria, particularly clinical CRAB isolates. Analyses of antimicrobial mechanisms based on lipopolysaccharide (LPS)-neutralization, LPS binding, and membrane depolarization, as well as SEM ultrastructural investigations, revealed that R-Pro9-3D binds strongly to LPS and impairs the membrane integrity of CRAB by effectively permeabilizing its outer membrane. R-Pro9-3D was also less cytotoxic and had better proteolytic stability than Pro9-3D and killed biofilm forming CRAB. As an LPS-neutralizing peptide, R-Pro9-3D effectively reduced LPS-induced pro-inflammatory cytokine levels in RAW 264.7 cells. The antiseptic abilities of R-Pro9-3D were also investigated using a mouse model of CRAB-induced sepsis, which revealed that R-Pro9-3D reduced multiple organ damage and attenuated systemic infection by acting as an antibacterial and immunosuppressive agent. Thus, R-Pro9-3D displays potential as a novel antiseptic peptide for treating Gram-negative CRAB infections.https://www.mdpi.com/1422-0067/22/22/12520antimicrobial peptide<i>A. baumannii</i>carbapenem-resistancesepsis |
| spellingShingle | Manigandan Krishnan Joonhyeok Choi Ahjin Jang Young Kyung Yoon Yangmee Kim Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection International Journal of Molecular Sciences antimicrobial peptide <i>A. baumannii</i> carbapenem-resistance sepsis |
| title | Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_full | Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_fullStr | Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_full_unstemmed | Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_short | Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant <i>Acinetobacter baumannii</i> Infection |
| title_sort | antiseptic 9 meric peptide with potency against carbapenem resistant i acinetobacter baumannii i infection |
| topic | antimicrobial peptide <i>A. baumannii</i> carbapenem-resistance sepsis |
| url | https://www.mdpi.com/1422-0067/22/22/12520 |
| work_keys_str_mv | AT manigandankrishnan antiseptic9mericpeptidewithpotencyagainstcarbapenemresistantiacinetobacterbaumanniiiinfection AT joonhyeokchoi antiseptic9mericpeptidewithpotencyagainstcarbapenemresistantiacinetobacterbaumanniiiinfection AT ahjinjang antiseptic9mericpeptidewithpotencyagainstcarbapenemresistantiacinetobacterbaumanniiiinfection AT youngkyungyoon antiseptic9mericpeptidewithpotencyagainstcarbapenemresistantiacinetobacterbaumanniiiinfection AT yangmeekim antiseptic9mericpeptidewithpotencyagainstcarbapenemresistantiacinetobacterbaumanniiiinfection |