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γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5

An increase in the number of infections caused by resistant bacteria worldwide necessitates the development of alternatives to antibiotics. Human defensin (HD) 5 is an innate immune peptide with broad-spectrum antibacterial activity, but its complicated structure makes its preparation difficult. Her...

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Autores principales: Zhao, Gaomei, Jia, Changsheng, Zhu, Cheng, Fang, Minchao, Li, Chenwenya, Chen, Yin, He, Yingjuan, Han, Songling, He, Yongwu, Gao, Jining, Wang, Tao, Wang, Cheng, Wang, Junping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9862697/
https://www.ncbi.nlm.nih.gov/pubmed/36676858
http://dx.doi.org/10.3390/membranes13010051
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author Zhao, Gaomei
Jia, Changsheng
Zhu, Cheng
Fang, Minchao
Li, Chenwenya
Chen, Yin
He, Yingjuan
Han, Songling
He, Yongwu
Gao, Jining
Wang, Tao
Wang, Cheng
Wang, Junping
author_facet Zhao, Gaomei
Jia, Changsheng
Zhu, Cheng
Fang, Minchao
Li, Chenwenya
Chen, Yin
He, Yingjuan
Han, Songling
He, Yongwu
Gao, Jining
Wang, Tao
Wang, Cheng
Wang, Junping
author_sort Zhao, Gaomei
collection PubMed
description An increase in the number of infections caused by resistant bacteria worldwide necessitates the development of alternatives to antibiotics. Human defensin (HD) 5 is an innate immune peptide with broad-spectrum antibacterial activity, but its complicated structure makes its preparation difficult. Herein, we truncated the HD5 structure by extracting the highly conserved γ-core motif. A structure-activity study showed that this motif was ineffective in killing bacteria in the absence of specific spatial conformation. Notably, after the introduction of two intramolecular disulfide bonds, its antibacterial activity was markedly improved. Glu and Ser residues were then replaced with Arg to create the derivative RC18, which exhibited stronger potency than HD5, particularly against methicillin-resistant S. aureus (MRSA). Mechanistically, RC18 bound to lipid A and lipoteichoic acid at higher affinities than HD5. Furthermore, RC18 was more efficient than HD5 in penetrating the bacterial membranes. Molecular dynamics simulation revealed that five Arg residues, Arg1, Arg7, Arg9, Arg15, and Arg18, mediated most of the polar interactions of RC18 with the phospholipid head groups during membrane penetration. In vivo experiments indicated that RC18 decreased MRSA colonization and dramatically improved the survival of infected mice, thus demonstrating that RC18 is a promising drug candidate to treat MRSA infections.
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spelling pubmed-98626972023-01-22 γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5 Zhao, Gaomei Jia, Changsheng Zhu, Cheng Fang, Minchao Li, Chenwenya Chen, Yin He, Yingjuan Han, Songling He, Yongwu Gao, Jining Wang, Tao Wang, Cheng Wang, Junping Membranes (Basel) Article An increase in the number of infections caused by resistant bacteria worldwide necessitates the development of alternatives to antibiotics. Human defensin (HD) 5 is an innate immune peptide with broad-spectrum antibacterial activity, but its complicated structure makes its preparation difficult. Herein, we truncated the HD5 structure by extracting the highly conserved γ-core motif. A structure-activity study showed that this motif was ineffective in killing bacteria in the absence of specific spatial conformation. Notably, after the introduction of two intramolecular disulfide bonds, its antibacterial activity was markedly improved. Glu and Ser residues were then replaced with Arg to create the derivative RC18, which exhibited stronger potency than HD5, particularly against methicillin-resistant S. aureus (MRSA). Mechanistically, RC18 bound to lipid A and lipoteichoic acid at higher affinities than HD5. Furthermore, RC18 was more efficient than HD5 in penetrating the bacterial membranes. Molecular dynamics simulation revealed that five Arg residues, Arg1, Arg7, Arg9, Arg15, and Arg18, mediated most of the polar interactions of RC18 with the phospholipid head groups during membrane penetration. In vivo experiments indicated that RC18 decreased MRSA colonization and dramatically improved the survival of infected mice, thus demonstrating that RC18 is a promising drug candidate to treat MRSA infections. MDPI 2022-12-31 /pmc/articles/PMC9862697/ /pubmed/36676858 http://dx.doi.org/10.3390/membranes13010051 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhao, Gaomei
Jia, Changsheng
Zhu, Cheng
Fang, Minchao
Li, Chenwenya
Chen, Yin
He, Yingjuan
Han, Songling
He, Yongwu
Gao, Jining
Wang, Tao
Wang, Cheng
Wang, Junping
γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5
title γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5
title_full γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5
title_fullStr γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5
title_full_unstemmed γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5
title_short γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5
title_sort γ-core guided antibiotic design based on human enteric defensin 5
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9862697/
https://www.ncbi.nlm.nih.gov/pubmed/36676858
http://dx.doi.org/10.3390/membranes13010051
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