The next generation of antimicrobial peptides (AMPs) as molecular therapeutic tools for the treatment of diseases with social and economic impacts

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Highlights

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Review of the present status of the development of antimicrobial peptides (AMPs).
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Recent advances in designing new anti-infective agents with enhanced activity.
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Transient expression of AMPs in tobacco to boost the biosynthesis of pharmaceutics.
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CRISPRs, an impressive genome editing tool to enhance the biosynthesis of new AMPs.

Abstract

Anti-infective drugs have had a key role in the contemporary world, contributing to dramatically decrease mortality rates caused by infectious diseases worldwide. Antimicrobial peptides (AMPs) are multifunctional effectors of the innate immune system of mucosal surfaces and present antimicrobial activity against a range of pathogenic viruses, bacteria, and fungi. However, the discovery and development of new antibacterial drugs is a crucial step to overcome the great challenge posed by the emergence of antibiotic resistance. In this review, we outline recent advances in the development of novel AMPs with improved antimicrobial activities that were achieved through characteristic structural design. In addition, we describe recent progress made to overcome some of the major limitations that have hindered peptide biosynthesis.

Abstract

This review provides an integrated scenario of the most relevant aspects in the development of useful drugs provided by natural sources and recent advances in the biosynthesis and structural design of antimicrobial peptides.

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Most cited references 80

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The expanding scope of antimicrobial peptide structures and their modes of action.

Leonard T. Nguyen, Evan Haney, Hans Vogel (2011)

Antimicrobial peptides (AMPs) are an integral part of the innate immune system that protect a host from invading pathogenic bacteria. To help overcome the problem of antimicrobial resistance, cationic AMPs are currently being considered as potential alternatives for antibiotics. Although extremely variable in length, amino acid composition and secondary structure, all peptides can adopt a distinct membrane-bound amphipathic conformation. Recent studies demonstrate that they achieve their antimicrobial activity by disrupting various key cellular processes. Some peptides can even use multiple mechanisms. Moreover, several intact proteins or protein fragments are now being shown to have inherent antimicrobial activity. A better understanding of the structure-activity relationships of AMPs is required to facilitate the rational design of novel antimicrobial agents. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Mechanisms and consequences of bacterial resistance to antimicrobial peptides.

D I Andersson, D D Hughes, J Kubicek-Sutherland (2016)

Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an alternative antibacterial therapy. Several cationic peptides that are derivatives of AMPs from the human innate immune system are currently in clinical development. There are also ongoing clinical studies aimed at modulating the expression of AMPs to boost the human innate immune response. In this review we discuss the potential problems associated with these therapeutic approaches. There is considerable experimental data describing mechanisms by which bacteria can develop resistance to AMPs. As for any type of drug resistance, the rate by which AMP resistance would emerge and spread in a population of bacteria in a natural setting will be determined by a complex interplay of several different factors, including the mutation supply rate, the fitness of the resistant mutant at different AMP concentrations, and the strength of the selective pressure. Several studies have already shown that AMP-resistant bacterial mutants display broad cross-resistance to a variety of AMPs with different structures and modes of action. Therefore, routine clinical administration of AMPs to treat bacterial infections may select for resistant bacterial pathogens capable of better evading the innate immune system. The ramifications of therapeutic levels of exposure on the development of AMP resistance and bacterial pathogenesis are not yet understood. This is something that needs to be carefully studied and monitored if AMPs are used in clinical settings.

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CRISPR/Cas9 for genome editing: progress, implications and challenges.

F Zhang, Y. Wen, X. Guo (2014)

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) protein 9 system provides a robust and multiplexable genome editing tool, enabling researchers to precisely manipulate specific genomic elements, and facilitating the elucidation of target gene function in biology and diseases. CRISPR/Cas9 comprises of a nonspecific Cas9 nuclease and a set of programmable sequence-specific CRISPR RNA (crRNA), which can guide Cas9 to cleave DNA and generate double-strand breaks at target sites. Subsequent cellular DNA repair process leads to desired insertions, deletions or substitutions at target sites. The specificity of CRISPR/Cas9-mediated DNA cleavage requires target sequences matching crRNA and a protospacer adjacent motif locating at downstream of target sequences. Here, we review the molecular mechanism, applications and challenges of CRISPR/Cas9-mediated genome editing and clinical therapeutic potential of CRISPR/Cas9 in future. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Author and article information

Contributors

Fabrício F. Costa

Journal

Journal ID (nlm-ta): Drug Discov Today

Journal ID (iso-abbrev): Drug Discov. Today

Title: Drug Discovery Today

Publisher: Elsevier Ltd.

ISSN (Print): 1359-6446

ISSN (Electronic): 1878-5832

Publication date PMC-release: 23 November 2016

Publication date (Print): February 2017

Publication date (Electronic): 23 November 2016

Volume: 22

Issue: 2

Pages: 234-248

Affiliations

[1 ]Center of Proteomic and Biochemical Analysis, Post-Graduation in Genomic Sciences and Biotechnology Universidade Católica de Brasília UCB, SGAN 916, Modulo B, Bloco C, 70.790-160 Brasilia, DF, Brazil

[2 ]Genomic Sciences and Biotechnology Program – Universidade Católica de Brasília UCB, SGAN 916, Modulo B, Bloco C, 70.790-160 Brasilia, DF, Brazil

[3 ]Universidade Ceuma, Rua Josué Montello, 1, 65060-645 São Luís, MA, Brazil

[4 ]Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, 02139 Cambridge, MA, USA

[5 ]Research Laboratory of Electronics, Massachusetts Institute of Technology, 02139 Cambridge, MA, USA

[6 ]Department of Biological Engineering, Massachusetts Institute of Technology, 02139 Cambridge, MA, USA

[7 ]Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, 02142 Cambridge, MA, USA

[8 ]Broad Institute of MIT and Harvard, 02142 Cambridge, MA, USA

[9 ]Harvard Biophysics Program, Harvard University, 02115 Boston, MA, USA

[10 ]S-Inova Biotech, Post-Graduation in Biotechnology, Universidade Católica Dom Bosco, 79117-900 Campo Grande, MS, Brazil

Author notes

[* ] Corresponding author: fcosta@ 123456genomicenterprise.com

Article

Publisher ID: S1359-6446(16)30413-5

DOI: 10.1016/j.drudis.2016.10.017

PMC ID: 7185764

PubMed ID: 27890668

SO-VID: 1ec36d18-987e-45dc-a74b-b44c9c2ab1f6

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Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

The next generation of antimicrobial peptides (AMPs) as molecular therapeutic tools for the treatment of diseases with social and economic impacts

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Neuropharmacology and Therapy

Most cited references 80

The expanding scope of antimicrobial peptide structures and their modes of action.

Mechanisms and consequences of bacterial resistance to antimicrobial peptides.

CRISPR/Cas9 for genome editing: progress, implications and challenges.

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