Peptide Design Principles for Antimicrobial Applications

doi:10.1016/j.jmb.2018.12.015

Journal of Molecular Biology

Volume 431, Issue 18, 23 August 2019, Pages 3547-3567

https://doi.org/10.1016/j.jmb.2018.12.015 Get rights and content

Highlights

•
Urgency for new antimicrobial agents to treat antibiotic-resistant microorganism-caused infections
•
Efficient design tools are needed for rational design of promising antibiotic candidates.
•
Physicochemical features are the basis for the most relevant activity descriptors of antimicrobial peptides.
•
Structure–activity relationships studies enable a wide range of commercial applications for antimicrobial peptides.

Abstract

The increased incidence of bacterial resistance to available antibiotics represents a major global health problem and highlights the need for novel anti-infective therapies. Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics. AMPs are versatile, have almost unlimited sequence space, and can be tuned for broad-spectrum or specific activity against microorganisms. However, several obstacles remain to be overcome in order to develop AMPs for medical use, such as toxicity, stability, and bacterial resistance. We lack standard experimental procedures for quantifying AMP activity and do not yet have a clear picture of the mechanisms of action of AMPs. The rational design of AMPs can help solve these issues and enable their use as new antimicrobials. Here we provide an overview of the main physicochemical features that can be engineered to achieve enhanced bioactivity and describe current strategies being used to design AMPs.

Graphical abstract

Section snippets

Antimicrobial Peptides

The current increase in multidrug-resistant bacteria is an alarming global health problem. In fact, antibiotic-resistant infections [1], [2] are expected to cause 10 million deaths annually by the year 2050 if no new antimicrobial approaches are implemented [3]. Antimicrobial peptides (AMPs), produced by virtually all organisms on Earth, offer an alternative to conventional antibiotics.

AMPs are part of the host's defense system. These agents are key components of the innate immune system of a

Strategies for Determining Structure–Activity Relationships

AMP structure–activity relationship (SAR) studies can be used to address ways to systematically modify naturally occurring molecules or de novo designed synthetic peptides and to determine both their structure and their biological activities. The overall aim is to maximize antimicrobial activity and resistance to proteolytic degradation while minimizing toxicity toward the host. The most well-known methodologies that have been used to design new AMPs and guide SAR studies are site-directed

Important Features for Peptide Design

The physicochemical properties of complex molecules are generally addressed by descriptors, which are computational vectors that provide information about physicochemical parameters of amino acids in a given peptide chain. As peptides are large and as they present secondary, and sometimes tertiary structures, they are considered complex molecules. Slight modifications in the amino acid composition can change the whole geometrical disposition and physicochemical properties of a peptide. Basic

Target and Application Design

The design of new synthetic AMPs, apart from increasing antimicrobial activity, aims to reconfigure peptides to achieve increased selectivity, resistance to degradation, and decreased hemolytic activity or cytotoxicity toward healthy cells. The frontiers and challenges for designing and eventually applying AMPs as novel therapies include obtaining precise control over such functions. Specificity is another major property that is increasingly being considered, as next-generation antimicrobials

Future Perspective

All the methods described above are useful depending on the kind of study and aims proposed. Mutagenesis and other traditional methods are still being used for their simplicity and effective results obtained, but as computational power has increased, in silico methods have provided the most commonly applied and precise techniques for bioactive peptide design. Additional computational tools such as neural networks, genetic algorithms, and machine learning are being developed, which leverage

Conclusions

Peptides are promising compounds not only for antimicrobial therapeutics but as immunomodulatory agents [190] and anticancer drugs [191]. The versatility and tenability of this class of molecules can be exploited to combat antibiotic resistance. In order to achieve high-quality design of peptides, the appropriate method should line up with the problem being addressed and the available options. Subsequently, important AMP features must be considered and included in the rationale. These compounds

Acknowledgments

Some of the figures shown here were prepared using the Motifolio drawing toolkit.

Cesar de la Fuente-Nunez acknowledges support by the Ramon Areces Foundation. Marcelo Der Torossian Torres was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (Brazil) (2014/04507-5 and 2016/24413-0), DTRA HDTRA (1-15-1-0050). Timothy K. Lu is supported by the National Institutes of Health, National Science Foundation, Defense Threat Reduction Agency, Defense Advanced Research Projects Agency,

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Journal of Molecular Biology

ReviewPeptide Design Principles for Antimicrobial Applications

Highlights

Abstract

Graphical abstract

Section snippets

Antimicrobial Peptides

Strategies for Determining Structure–Activity Relationships

Important Features for Peptide Design

Target and Application Design

Future Perspective

Conclusions

Acknowledgments

Curr. Opin. Microbiol.

Trends Microbiol.

Trends Biotechnol.

Chem. Sci.

Biochim. Biophys. Acta Biomembr.

Biochim. Biophys. Acta Biomembr.

Chem. Phys. Lipids

Biochim. Biophys. Acta Biomembr.

Biochim. Biophys. Acta Biomembr.

Biophys. J.

Biochim. Biophys. Acta Biomembr.

Biochem. Biophys. Res. Commun.

Prostaglandins Leukot. Essent. Fatty Acids

FEMS Microbiol. Lett.

Biochim. Biophys. Acta Biomembr.

Food Chem. Toxicol.

Food Chem.

Biochim. Biophys. Acta Biomembr.

Biochim. Biophys. Acta Biomembr.

J. Colloid Interface Sci.

Biochim. Biophys. Acta Biomembr.

Arch. Oral Biol.

Eur. J. Med. Chem.

Biochim. Biophys. Acta Biomembr.

Drug Discov. Today

Biotechnol. Adv.

Biochim. Biophys. Acta Biomembr.

Curr. Opin. Chem. Biol.

Biochim. Biophys. Acta Biomembr.

Chem. Biol.

Biotechnol. Adv.

The Review on Antimicrobial Resistance Chaired by Jim O'Neill December 2014

Membrane-active antimicrobial peptides as template structures for novel antibiotic agents

Curr. Top. Med. Chem.

Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?

Nat. Rev. Microbiol.

Binding modes of teixobactin to lipid II: molecular dynamics study

Sci. Rep.

Copsin, a novel peptide-based fungal antibiotic interfering with the peptidoglycan synthesis

J. Biol. Chem.

An alternative bactericidal mechanism of action for lantibiotic peptides that target lipid II

Science

New strategies for novel antibiotics: peptides targeting bacterial cell membranes

Gen. Physiol. Biophys.

Bacterial membrane lipids in the action of antimicrobial agents

J. Pept. Sci.

Lactoferricin: a lactoferrin-derived peptide with antimicrobial, antiviral, antitumor and immunological properties

Cell. Mol. Life Sci.

Lipid topology and electrostatic interactions underpin lytic activity of linear cationic antimicrobial peptides in membranes

Proc. Natl. Acad. Sci.

Modulation of membrane curvature by peptides

Pept. Sci.

Modulation of the spontaneous curvature and bending rigidity of lipid membranes by interfacially adsorbed amphipathic peptides

J. Phys. Chem. B

Transcriptome analysis of Streptococcus pneumoniae treated with the designed antimicrobial peptides

DM3

Sirtuin 6 plays an oncogenic role and induces cell autophagy in esophageal cancer cells

Tumor Biol.

Evaluation of the Immunomodulatory Activity of the Chicken NK-Lysin-Derived Peptide cNK-2

Sci Rep

Anti-biofilm and immunomodulatory activities of peptides that inhibit biofilms formed by pathogens isolated from cystic fibrosis patients

Antibiotics (Basel, Switzerland)

Short proline-rich antimicrobial peptides inhibit either the bacterial 70S ribosome or the assembly of its large 50S subunit

Chembiochem

Antimicrobial peptides: an alternative for innovative medicines?

Appl. Microbiol. Biotechnol.

Soypeptide lunasin in cytokine immunotherapy for lymphoma

Review
Peptide Design Principles for Antimicrobial Applications