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Novel Antibacterials: Antimicrobial Peptides, Peptidomimetics and Conjugates

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 28810

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Prof. Dr. Paul Robert Hansen

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Guest Editor

Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Interests: antimicrobial peptides; drug delivery
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Henrik Franzyk

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Guest Editor

Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Interests: antimicrobial peptides; immunomodulation; drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The use of antibiotics to treat life-threatening infectious diseases has saved millions of lives for nearly a century. However, multidrug-resistant bacterial strains are continuously arising so that it now constitutes a global health crisis. Thus, there is an urgent need to identify new molecules and therapies to combat multidrug-resistant bacteria. Antimicrobial peptides (AMPs) play a key role in the innate immune system of higher organisms. Currently, AMPs receive considerable attention as potential antibiotics, since they are active against both Gram-positive and Gram-negative pathogens (typically at low micromolar concentrations) and act via rapid killing modes targeting the bacterial membrane, which makes resistance development slower. However, the use of AMPs as clinical therapeutics has been hampered by their low bioavailibity and metabolic instability. A strategy to circumvent these drawbacks is to use AMPs as starting points for design of peptide mimics (i.e., peptidomimetics) with improved activity profiles and stability. Potent peptidomimetics have been discovered using several approaches, e.g., involving incorporation of nonstandard amino acids or alternative backbone structures, as well as antibacterial conjugates comprising combinations of antibiotics, siderophores, peptides, peptidomimetics, peptide nucleic acids, and natural products. For this Special Issue entitled” "Novel Antibacterials: Antimicrobial Peptides, Peptidomimetics, and Conjugates”, we invite authors to submit articles covering all aspects of this theme.

Prof. Dr. Paul Robert Hansen
Prof. Dr. Henrik Franzyk
Guest Editors

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Keywords

Antimicrobial peptides
Peptidomimetics
Antibacterial conjugates
Structure-activity studies
Multidrug-resistant bacteria
Human pathogens

Published Papers (6 papers)

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Research

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9 pages, 9182 KiB

Open AccessArticle

Development of Antimicrobial Stapled Peptides Based on Magainin 2 Sequence

by Motoharu Hirano, Chihiro Saito, Hidetomo Yokoo, Chihiro Goto, Ryuji Kawano, Takashi Misawa and Yosuke Demizu

Molecules 2021, 26(2), 444; https://doi.org/10.3390/molecules26020444 - 16 Jan 2021

Cited by 27 | Viewed by 3874

Abstract

Magainin 2 (Mag2), which was isolated from the skin of the African clawed frog, is a representative antimicrobial peptide (AMP) that exerts antimicrobial activity via microbial membrane disruption. It has been reported that the helicity and amphipathicity of Mag2 play important roles in its antimicrobial activity. We investigated and recently reported that 17 amino acid residues of Mag2 are required for its antimicrobial activity, and accordingly developed antimicrobial foldamers containing α,α-disubstituted amino acid residues. In this study, we further designed and synthesized a set of Mag2 derivatives bearing the hydrocarbon stapling side chain for helix stabilization. The preferred secondary structures, antimicrobial activities, and cell-membrane disruption activities of the synthesized peptides were evaluated. Our analyses revealed that hydrocarbon stapling strongly stabilized the helical structure of the peptides and enhanced their antimicrobial activity. Moreover, peptide 2 stapling between the first and fifth position from the N-terminus showed higher antimicrobial activity than that of Mag2 against both gram-positive and gram-negative bacteria without exerting significant hemolytic activity. To investigate the modes of action of tested peptides 2 and 8 in antimicrobial and hemolytic activity, electrophysiological measurements were performed. Full article

(This article belongs to the Special Issue Novel Antibacterials: Antimicrobial Peptides, Peptidomimetics and Conjugates)

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16 pages, 4264 KiB

Open AccessArticle

Covalently Immobilized Battacin Lipopeptide Gels with Activity against Bacterial Biofilms

by Gayan Heruka De Zoysa, Kelvin Wang, Jun Lu, Yacine Hemar and Vijayalekshmi Sarojini

Molecules 2020, 25(24), 5945; https://doi.org/10.3390/molecules25245945 - 15 Dec 2020

Cited by 7 | Viewed by 1970

Abstract

Novel antibiotic treatments are in increasing demand to tackle life-threatening infections from bacterial pathogens. In this study, we report the use of a potent battacin lipopeptide as an antimicrobial gel to inhibit planktonic and mature biofilms of S. aureus and P. aeruginosa. The antimicrobial gels were made by covalently linking the N-terminal cysteine containing lipopeptide (GZ3.163) onto the polyethylene glycol polymer matrix and initiating gelation using thiol-ene click chemistry. The gels were prepared both in methanol and in water and were characterised using rheology, Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). Antibacterial and antibiofilm analyses revealed that the gels prepared in methanol have better antibacterial and antibiofilm activity. Additionally, a minimum peptide content of 0.5 wt% (relative to polymer content) is required to successfully inhibit the planktonic bacterial growth and disperse mature biofilms of P. aeruginosa and S. aureus. The antibacterial activity of these lipopeptide gels is mediated by a contact kill mechanism of action. The gels are non-haemolytic against mouse red blood cells and are non-cytotoxic against human dermal fibroblasts. Findings from this study show that battacin lipopeptide gels have the potential to be developed as novel topical antibacterial agents to combat skin infections, particularly caused by S. aureus. Full article

(This article belongs to the Special Issue Novel Antibacterials: Antimicrobial Peptides, Peptidomimetics and Conjugates)

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12 pages, 1030 KiB

Open AccessArticle

Synergistic Effect of Propidium Iodide and Small Molecule Antibiotics with the Antimicrobial Peptide Dendrimer G3KL against Gram-Negative Bacteria

by Bee-Ha Gan, Xingguang Cai, Sacha Javor, Thilo Köhler and Jean-Louis Reymond

Molecules 2020, 25(23), 5643; https://doi.org/10.3390/molecules25235643 - 30 Nov 2020

Cited by 16 | Viewed by 3737

Abstract

There is an urgent need to develop new antibiotics against multidrug-resistant bacteria. Many antimicrobial peptides (AMPs) are active against such bacteria and often act by destabilizing membranes, a mechanism that can also be used to permeabilize bacteria to other antibiotics, resulting in synergistic effects. We recently showed that G3KL, an AMP with a multibranched dendritic topology of the peptide chain, permeabilizes the inner and outer membranes of Gram-negative bacteria including multidrug-resistant strains, leading to efficient bacterial killing. Here, we show that permeabilization of the outer and inner membranes of Pseudomonas aeruginosa by G3KL, initially detected using the DNA-binding fluorogenic dye propidium iodide (PI), also leads to a synergistic effect between G3KL and PI in this bacterium. We also identify a synergistic effect between G3KL and six different antibiotics against the Gram-negative Klebsiella pneumoniae, against which G3KL is inactive. Full article

(This article belongs to the Special Issue Novel Antibacterials: Antimicrobial Peptides, Peptidomimetics and Conjugates)

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21 pages, 1722 KiB

Open AccessArticle

The Spectrum of Design Solutions for Improving the Activity-Selectivity Product of Peptide Antibiotics against Multidrug-Resistant Bacteria and Prostate Cancer PC-3 Cells

by Davor Juretić, Anja Golemac, Denise E. Strand, Keshi Chung, Nada Ilić, Ivana Goić-Barišić and François-Xavier Pellay

Molecules 2020, 25(15), 3526; https://doi.org/10.3390/molecules25153526 - 01 Aug 2020

Cited by 6 | Viewed by 3488

Abstract

The link between the antimicrobial and anticancer activity of peptides has long been studied, and the number of peptides identified with both activities has recently increased considerably. In this work, we hypothesized that designed peptides with a wide spectrum of selective antimicrobial activity will also have anticancer activity, and tested this hypothesis with newly designed peptides. The spectrum of peptides, used as partial or full design templates, ranged from cell-penetrating peptides and putative bacteriocin to those from the simplest animals (placozoans) and the Chordata phylum (anurans). We applied custom computational tools to predict amino acid substitutions, conferring the increased product of bacteriostatic activity and selectivity. Experiments confirmed that better overall performance was achieved with respect to that of initial templates. Nine of our synthesized helical peptides had excellent bactericidal activity against both standard and multidrug-resistant bacteria. These peptides were then compared to a known anticancer peptide polybia-MP1, for their ability to kill prostate cancer cells and dermal primary fibroblasts. The therapeutic index was higher for seven of our peptides, and anticancer activity stronger for all of them. In conclusion, the peptides that we designed for selective antimicrobial activity also have promising potential for anticancer applications. Full article

(This article belongs to the Special Issue Novel Antibacterials: Antimicrobial Peptides, Peptidomimetics and Conjugates)

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Review

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15 pages, 2420 KiB

Open AccessReview

Lactoferrin: A Glycoprotein Involved in Immunomodulation, Anticancer, and Antimicrobial Processes

by Quintín Rascón-Cruz, Edward A. Espinoza-Sánchez, Tania S. Siqueiros-Cendón, Sayuri I. Nakamura-Bencomo, Sigifredo Arévalo-Gallegos and Blanca F. Iglesias-Figueroa

Molecules 2021, 26(1), 205; https://doi.org/10.3390/molecules26010205 - 03 Jan 2021

Cited by 45 | Viewed by 7148

Abstract

Lactoferrin is an iron binding glycoprotein with multiple roles in the body. Its participation in apoptotic processes in cancer cells, its ability to modulate various reactions of the immune system, and its activity against a broad spectrum of pathogenic microorganisms, including respiratory viruses, have made it a protein of broad interest in pharmaceutical and food research and industry. In this review, we have focused on describing the most important functions of lactoferrin and the possible mechanisms of action that lead to its function. Full article

(This article belongs to the Special Issue Novel Antibacterials: Antimicrobial Peptides, Peptidomimetics and Conjugates)

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48 pages, 2856 KiB

Open AccessReview

Lactoferrin and Its Derived Peptides: An Alternative for Combating Virulence Mechanisms Developed by Pathogens

by Daniela Zarzosa-Moreno, Christian Avalos-Gómez, Luisa Sofía Ramírez-Texcalco, Erick Torres-López, Ricardo Ramírez-Mondragón, Juan Omar Hernández-Ramírez, Jesús Serrano-Luna and Mireya de la Garza

Molecules 2020, 25(24), 5763; https://doi.org/10.3390/molecules25245763 - 08 Dec 2020

Cited by 45 | Viewed by 7821

Abstract

Due to the emergence of multidrug-resistant pathogens, it is necessary to develop options to fight infections caused by these agents. Lactoferrin (Lf) is a cationic nonheme multifunctional glycoprotein of the innate immune system of mammals that provides numerous benefits. Lf is bacteriostatic and/or bactericidal, can stimulate cell proliferation and differentiation, facilitate iron absorption, improve neural development and cognition, promote bone growth, prevent cancer and exert anti-inflammatory and immunoregulatory effects. Lactoferrin is present in colostrum and milk and is also produced by the secondary granules of polymorphonuclear leukocytes, which store this glycoprotein and release it at sites of infection. Lf is also present in many fluids and exocrine secretions, on the surfaces of the digestive, respiratory and reproductive systems that are commonly exposed to pathogens. Apo-Lf (an iron-free molecule) can be microbiostatic due to its ability to capture ferric iron, blocking the availability of host iron to pathogens. However, apo-Lf is mostly microbicidal via its interaction with the microbial surface, causing membrane damage and altering its permeability function. Lf can inhibit viral entry by binding to cell receptors or viral particles. Lf is also able to counter different important mechanisms evolved by microbial pathogens to infect and invade the host, such as adherence, colonization, invasion, production of biofilms and production of virulence factors such as proteases and toxins. Lf can also cause mitochondrial and caspase-dependent regulated cell death and apoptosis-like in pathogenic yeasts. All of these mechanisms are important targets for treatment with Lf. Holo-Lf (the iron-saturated molecule) can contain up to two ferric ions and can also be microbicidal against some pathogens. On the other hand, lactoferricins (Lfcins) are peptides derived from the N-terminus of Lf that are produced by proteolysis with pepsin under acidic conditions, and they cause similar effects on pathogens to those caused by the parental Lf. Synthetic analog peptides comprising the N-terminus Lf region similarly exhibit potent antimicrobial properties. Importantly, there are no reported pathogens that are resistant to Lf and Lfcins; in addition, Lf and Lfcins have shown a synergistic effect with antimicrobial and antiviral drugs. Due to the Lf properties being microbiostatic, microbicidal, anti-inflammatory and an immune modulator, it represents an excellent natural alternative either alone or as adjuvant in the combat to antibiotic multidrug-resistant bacteria and other pathogens. This review aimed to evaluate the data that appeared in the literature about the effects of Lf and its derived peptides on pathogenic bacteria, protozoa, fungi and viruses and how Lf and Lfcins inhibit the mechanisms developed by these pathogens to cause disease. Full article

(This article belongs to the Special Issue Novel Antibacterials: Antimicrobial Peptides, Peptidomimetics and Conjugates)

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