Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability
Abstract Cathelicidins are regarded as promising antibiotics due to their capability against antibiotic-resistant bacteria without cytotoxicity. However, some concerns about the balance of cytotoxicity and antimicrobial activity, weak stability and enzymatic susceptibility sually restrict their ther...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-02050-2 |
| _version_ | 1818345155039592448 |
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| author | Haining Yu Chen Wang Lan Feng Shasha Cai Xuelian Liu Xue Qiao Nannan Shi Hui Wang Yipeng Wang |
| author_facet | Haining Yu Chen Wang Lan Feng Shasha Cai Xuelian Liu Xue Qiao Nannan Shi Hui Wang Yipeng Wang |
| author_sort | Haining Yu |
| collection | DOAJ |
| description | Abstract Cathelicidins are regarded as promising antibiotics due to their capability against antibiotic-resistant bacteria without cytotoxicity. However, some concerns about the balance of cytotoxicity and antimicrobial activity, weak stability and enzymatic susceptibility sually restrict their therapeutic use. Here, we designed a series of shortened variants, Hc1~15, based on our previously characterized Hc-CATH. Hc3, the one with the best activity, after point mutation was engineered with a trypsin inhibitor loop, ORB-C, to obtain four hybrid peptides: H3TI, TIH3, H3TIF and TIH3F. All four except TIH3 were found possessing an appreciable profile of proteases inhibitory and antimicrobial characteristics without increase in cytotoxicity. Among them, TIH3F exhibited the most potent and broad-spectrum antimicrobial and anti-inflammatory activities. Fluorescence spectroscopy has demonstrated a quick induction of bacterial membrane permeability by TIH3F leading to the cell death, which also accounts for its fast anti-biofilm activity. Such mode of antimicrobial action was mainly attributed to peptides’ amphiphilic and helical structures determined by CD and homology modeling. Besides, TIH3F exhibited good tolerance to salt, serum, pH, and temperature, indicating a much better physiological stability in vitro than Hc3, Most importantly, in the case of resistance against proteases hydrolysis, current hybrid peptides displayed a remarkable enhancement than their original templates. |
| first_indexed | 2024-12-13T16:57:52Z |
| format | Article |
| id | doaj.art-884ed1076d314f5a9a398111c36c622f |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-13T16:57:52Z |
| publishDate | 2017-06-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-884ed1076d314f5a9a398111c36c622f2022-12-21T23:37:53ZengNature PortfolioScientific Reports2045-23222017-06-017111810.1038/s41598-017-02050-2Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stabilityHaining Yu0Chen Wang1Lan Feng2Shasha Cai3Xuelian Liu4Xue Qiao5Nannan Shi6Hui Wang7Yipeng Wang8School of Life Science and Biotechnology, Dalian University of TechnologySchool of Life Science and Biotechnology, Dalian University of TechnologySchool of Life Science and Biotechnology, Dalian University of TechnologySchool of Life Science and Biotechnology, Dalian University of TechnologySchool of Life Science and Biotechnology, Dalian University of TechnologySchool of Life Science and Biotechnology, Dalian University of TechnologySchool of Life Science and Biotechnology, Dalian University of TechnologySchool of Life Science and Biotechnology, Dalian University of TechnologyDepartment of Pharmaceutical Sciences, College of Pharmaceutical Sciences, Soochow UniversityAbstract Cathelicidins are regarded as promising antibiotics due to their capability against antibiotic-resistant bacteria without cytotoxicity. However, some concerns about the balance of cytotoxicity and antimicrobial activity, weak stability and enzymatic susceptibility sually restrict their therapeutic use. Here, we designed a series of shortened variants, Hc1~15, based on our previously characterized Hc-CATH. Hc3, the one with the best activity, after point mutation was engineered with a trypsin inhibitor loop, ORB-C, to obtain four hybrid peptides: H3TI, TIH3, H3TIF and TIH3F. All four except TIH3 were found possessing an appreciable profile of proteases inhibitory and antimicrobial characteristics without increase in cytotoxicity. Among them, TIH3F exhibited the most potent and broad-spectrum antimicrobial and anti-inflammatory activities. Fluorescence spectroscopy has demonstrated a quick induction of bacterial membrane permeability by TIH3F leading to the cell death, which also accounts for its fast anti-biofilm activity. Such mode of antimicrobial action was mainly attributed to peptides’ amphiphilic and helical structures determined by CD and homology modeling. Besides, TIH3F exhibited good tolerance to salt, serum, pH, and temperature, indicating a much better physiological stability in vitro than Hc3, Most importantly, in the case of resistance against proteases hydrolysis, current hybrid peptides displayed a remarkable enhancement than their original templates.https://doi.org/10.1038/s41598-017-02050-2 |
| spellingShingle | Haining Yu Chen Wang Lan Feng Shasha Cai Xuelian Liu Xue Qiao Nannan Shi Hui Wang Yipeng Wang Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability Scientific Reports |
| title | Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability |
| title_full | Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability |
| title_fullStr | Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability |
| title_full_unstemmed | Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability |
| title_short | Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability |
| title_sort | cathelicidin trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability |
| url | https://doi.org/10.1038/s41598-017-02050-2 |
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