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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Autores principales:	Haining Yu, Chen Wang, Lan Feng, Shasha Cai, Xuelian Liu, Xue Qiao, Nannan Shi, Hui Wang, Yipeng Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/884ed1076d314f5a9a398111c36c622f
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spelling	oai:doaj.org-article:884ed1076d314f5a9a398111c36c622f2021-12-02T15:05:31ZCathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability10.1038/s41598-017-02050-22045-2322https://doaj.org/article/884ed1076d314f5a9a398111c36c622f2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02050-2https://doaj.org/toc/2045-2322Abstract 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.Haining YuChen WangLan FengShasha CaiXuelian LiuXue QiaoNannan ShiHui WangYipeng WangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-18 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	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_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_sort	cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/884ed1076d314f5a9a398111c36c622f
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_version_	1718388777259368448

Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability

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