Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS

Antimicrobial peptides (AMPs) are a promising class of compounds being developed against multi-drug resistant bacteria. Hybridization has been reported to increase antimicrobial activity. Here, two proline-rich peptides (consP1: VRKPPYLPRPRPRPL-CONH2 and Bac5-v291: RWRRPIRRRPIRPPFWR-CONH2) were comb...

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Autores principales:	Kai Hilpert, Jurnorain Gani, Christoph Rumancev, Nathan Simpson, Paula Matilde Lopez-Perez, Vasil M. Garamus, Andreas Robert von Gundlach, Petar Markov, Marco Scocchi, Ralf Mikut, Axel Rosenhahn
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	antimicrobial peptide hybrid peptide BioSAXS multi-drug resistance antimicrobial compound mode of action Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/3eea9ed054df43e8ab7a3bde63e39013
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spelling	oai:doaj.org-article:3eea9ed054df43e8ab7a3bde63e390132021-12-03T06:39:33ZRational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS1663-981210.3389/fphar.2021.769739https://doaj.org/article/3eea9ed054df43e8ab7a3bde63e390132021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.769739/fullhttps://doaj.org/toc/1663-9812Antimicrobial peptides (AMPs) are a promising class of compounds being developed against multi-drug resistant bacteria. Hybridization has been reported to increase antimicrobial activity. Here, two proline-rich peptides (consP1: VRKPPYLPRPRPRPL-CONH2 and Bac5-v291: RWRRPIRRRPIRPPFWR-CONH2) were combined with two arginine-isoleucine-rich peptides (optP1: KIILRIRWR-CONH2 and optP7: KRRVRWIIW-CONH2). Proline-rich antimicrobial peptides (PrAMPs) are known to inhibit the bacterial ribosome, shown also for Bac5-v291, whereas it is hypothesized a “dirty drug” model for the arginine-isoleucine-rich peptides. That hypothesis was underpinned by transmission electron microscopy and biological small-angle X-ray scattering (BioSAXS). The strength of BioSAXS is the power to detect ultrastructural changes in millions of cells in a short time (seconds) in a high-throughput manner. This information can be used to classify antimicrobial compounds into groups according to the ultrastructural changes they inflict on bacteria and how the bacteria react towards that assault. Based on previous studies, this correlates very well with different modes of action. Due to the novelty of this approach direct identification of the target of the antimicrobial compound is not yet fully established, more research is needed. More research is needed to address this limitation. The hybrid peptides showed a stronger antimicrobial activity compared to the proline-rich peptides, except when compared to Bac5-v291 against E. coli. The increase in activity compared to the arginine-isoleucine-rich peptides was up to 6-fold, however, it was not a general increase but was dependent on the combination of peptides and bacteria. BioSAXS experiments revealed that proline-rich peptides and arginine-isoleucine-rich peptides induce very different ultrastructural changes in E. coli, whereas a hybrid peptide (hyP7B5GK) shows changes, different to both parental peptides and the untreated control. These different ultrastructural changes indicated that the mode of action of the parental peptides might be different from each other as well as from the hybrid peptide hyP7B5GK. All peptides showed very low haemolytic activity, some of them showed a 100-fold or larger therapeutic window, demonstrating the potential for further drug development.Kai HilpertJurnorain GaniChristoph RumancevNathan SimpsonPaula Matilde Lopez-PerezVasil M. GaramusAndreas Robert von GundlachPetar MarkovMarco ScocchiRalf MikutAxel RosenhahnFrontiers Media S.A.articleantimicrobial peptidehybrid peptideBioSAXSmulti-drug resistanceantimicrobial compoundmode of actionTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial peptide hybrid peptide BioSAXS multi-drug resistance antimicrobial compound mode of action Therapeutics. Pharmacology RM1-950
spellingShingle	antimicrobial peptide hybrid peptide BioSAXS multi-drug resistance antimicrobial compound mode of action Therapeutics. Pharmacology RM1-950 Kai Hilpert Jurnorain Gani Christoph Rumancev Nathan Simpson Paula Matilde Lopez-Perez Vasil M. Garamus Andreas Robert von Gundlach Petar Markov Marco Scocchi Ralf Mikut Axel Rosenhahn Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS
description	Antimicrobial peptides (AMPs) are a promising class of compounds being developed against multi-drug resistant bacteria. Hybridization has been reported to increase antimicrobial activity. Here, two proline-rich peptides (consP1: VRKPPYLPRPRPRPL-CONH2 and Bac5-v291: RWRRPIRRRPIRPPFWR-CONH2) were combined with two arginine-isoleucine-rich peptides (optP1: KIILRIRWR-CONH2 and optP7: KRRVRWIIW-CONH2). Proline-rich antimicrobial peptides (PrAMPs) are known to inhibit the bacterial ribosome, shown also for Bac5-v291, whereas it is hypothesized a “dirty drug” model for the arginine-isoleucine-rich peptides. That hypothesis was underpinned by transmission electron microscopy and biological small-angle X-ray scattering (BioSAXS). The strength of BioSAXS is the power to detect ultrastructural changes in millions of cells in a short time (seconds) in a high-throughput manner. This information can be used to classify antimicrobial compounds into groups according to the ultrastructural changes they inflict on bacteria and how the bacteria react towards that assault. Based on previous studies, this correlates very well with different modes of action. Due to the novelty of this approach direct identification of the target of the antimicrobial compound is not yet fully established, more research is needed. More research is needed to address this limitation. The hybrid peptides showed a stronger antimicrobial activity compared to the proline-rich peptides, except when compared to Bac5-v291 against E. coli. The increase in activity compared to the arginine-isoleucine-rich peptides was up to 6-fold, however, it was not a general increase but was dependent on the combination of peptides and bacteria. BioSAXS experiments revealed that proline-rich peptides and arginine-isoleucine-rich peptides induce very different ultrastructural changes in E. coli, whereas a hybrid peptide (hyP7B5GK) shows changes, different to both parental peptides and the untreated control. These different ultrastructural changes indicated that the mode of action of the parental peptides might be different from each other as well as from the hybrid peptide hyP7B5GK. All peptides showed very low haemolytic activity, some of them showed a 100-fold or larger therapeutic window, demonstrating the potential for further drug development.
format	article
author	Kai Hilpert Jurnorain Gani Christoph Rumancev Nathan Simpson Paula Matilde Lopez-Perez Vasil M. Garamus Andreas Robert von Gundlach Petar Markov Marco Scocchi Ralf Mikut Axel Rosenhahn
author_facet	Kai Hilpert Jurnorain Gani Christoph Rumancev Nathan Simpson Paula Matilde Lopez-Perez Vasil M. Garamus Andreas Robert von Gundlach Petar Markov Marco Scocchi Ralf Mikut Axel Rosenhahn
author_sort	Kai Hilpert
title	Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS
title_short	Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS
title_full	Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS
title_fullStr	Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS
title_full_unstemmed	Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS
title_sort	rational designed hybrid peptides show up to a 6-fold increase in antimicrobial activity and demonstrate different ultrastructural changes as the parental peptides measured by biosaxs
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/3eea9ed054df43e8ab7a3bde63e39013
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Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS

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