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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 24131

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Prof. Dr. Gábor Tóth

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Department of Medical Chemistry, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary
Interests: protein and peptide synthesis; protein bioconjugation; bioactive peptides; bioorganic chemistry; synthesis of multiple disulfide containing polypeptides; posttranslationally modified peptides; ion channel blockers
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Dr. Györgyi Váradi

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Department of Medical Chemistry, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary
Interests: antimicrobial peptides; antifungal proteins; structure-activity relationships of antifungal proteins; peptide and protein synthesis; native chemical ligation; selective formation of disulfide bridges
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antibiotic resistance—when germs (bacteria and fungi) develop the ability to defeat the antibiotics designed to kill them—is one of the greatest global health challenges of modern time. Currently, at least 700,000 people die each year due to drug-resistant diseases, including 230,000 people who die from multidrug-resistant tuberculosis. More and more common diseases, including respiratory tract infections, sexually transmitted infections and urinary tract infections, are untreatable. The ever-increasing episodes of antibiotic resistance in bacteria and other microorganisms pose a serious threat to human health. Antimicrobial peptides (AMPs) are ribosomally synthesized natural antibiotics produced by nearly all organisms, from bacteria to plants and animals. AMPs are the first line of innate defense present in most living organisms, from bacteria to humans, against invading pathogens. Certain AMPs show an exceptionally broad spectrum of activity against Gram-negative and Gram-positive bacteria and fungi as well as viruses and parasites. Therefore, AMPs or their derivatives may represent potentially new classes of antimicrobial drugs. In this context, antimicrobial peptides (AMPs) have emerged as promising alternatives owing to their unique structural and functional characteristics. They have various modes of action; this diversity in the activity of the AMPs lead to the very-slow or negligible development of resistance against them in contrast to conventional antibiotics, which generally have a fixed intracellular target. This has led to significant advances in the area of AMP research in the last few decades for potential drugs of the future.

Prof. Dr. Gábor Tóth
Dr. Györgyi Váradi
Guest Editors

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

4 pages, 224 KiB

Open AccessEditorial

Rationally Designed Antimicrobial Peptides Are Potential Tools to Combat Devastating Bacteria and Fungi

by Györgyi Váradi, László Galgóczy and Gábor K. Tóth

Int. J. Mol. Sci. 2022, 23(11), 6244; https://doi.org/10.3390/ijms23116244 - 2 Jun 2022

Cited by 1 | Viewed by 1500

Abstract

The introduction of the first antibiotic (penicillin) by Sir Alexander Fleming in 1928 was a huge milestone in the treatment of infectious diseases [...] Full article

(This article belongs to the Special Issue Peptide Antimicrobial Agents)

Research

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14 pages, 2137 KiB

Open AccessArticle

Effects of Lipidation on a Proline-Rich Antibacterial Peptide

by Federica Armas, Adriana Di Stasi, Mario Mardirossian, Antonello A. Romani, Monica Benincasa and Marco Scocchi

Int. J. Mol. Sci. 2021, 22(15), 7959; https://doi.org/10.3390/ijms22157959 - 26 Jul 2021

Cited by 25 | Viewed by 2278

Abstract

The emergence of multidrug-resistant bacteria is a worldwide health problem. Antimicrobial peptides have been recognized as potential alternatives to conventional antibiotics, but still require optimization. The proline-rich antimicrobial peptide Bac7(1-16) is active against only a limited number of Gram-negative bacteria. It kills bacteria by inhibiting protein synthesis after its internalization, which is mainly supported by the bacterial transporter SbmA. In this study, we tested two different lipidated forms of Bac7(1-16) with the aim of extending its activity against those bacterial species that lack SbmA. We linked a C12-alkyl chain or an ultrashort cationic lipopeptide Lp-I to the C-terminus of Bac7(1-16). Both the lipidated Bac-C12 and Bac-Lp-I forms acquired activity at low micromolar MIC values against several Gram-positive and Gram-negative bacteria. Moreover, unlike Bac7(1-16), Bac-C12, and Bac-Lp-I did not select resistant mutants in E. coli after 14 times of exposure to sub-MIC concentrations of the respective peptide. We demonstrated that the extended spectrum of activity and absence of de novo resistance are likely related to the acquired capability of the peptides to permeabilize cell membranes. These results indicate that C-terminal lipidation of a short proline-rich peptide profoundly alters its function and mode of action and provides useful insights into the design of novel broad-spectrum antibacterial agents. Full article

(This article belongs to the Special Issue Peptide Antimicrobial Agents)

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21 pages, 4748 KiB

Open AccessArticle

Antimicrobial and Anti-Biofilm Peptide Octominin for Controlling Multidrug-Resistant Acinetobacter baumannii

by E. H. T. Thulshan Jayathilaka, Dinusha C. Rajapaksha, Chamilani Nikapitiya, Mahanama De Zoysa and Ilson Whang

Int. J. Mol. Sci. 2021, 22(10), 5353; https://doi.org/10.3390/ijms22105353 - 19 May 2021

Cited by 34 | Viewed by 4201

Abstract

Acinetobacter baumannii is a serious nosocomial pathogen with multiple drug resistance (MDR), the control of which has become challenging due to the currently used antibiotics. Our main objective in this study is to determine the antibacterial and antibiofilm activities of the antimicrobial peptide, Octominin, against MDR A. baumannii and derive its possible modes of actions. Octominin showed significant bactericidal effects at a low minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of 5 and 10 µg/mL, respectively. Time-kill kinetic analysis and bacterial viability tests revealed that Octominin showed a concentration-dependent antibacterial activity. Field-emission scanning electron microscopy (FE-SEM) analysis revealed that Octominin treatment altered the morphology and membrane structure of A. baumannii. Propidium iodide (PI) and reactive oxygen species (ROS) generation assays showed that Octominin increased the membrane permeability and ROS generation in A. baumannii, thereby causing bacterial cell death. Further, a lipopolysaccharides (LPS) binding assay showed an Octominin concentration-dependent LPS neutralization ability. Biofilm formation inhibition and eradication assays further revealed that Octominin inhibited biofilm formation and showed a high biofilm eradication activity against A. baumannii. Furthermore, up to a concentration of 100 µg/mL, Octominin caused no hemolysis and cell viability changes in mammalian cells. An in vivo study in zebrafish showed that the Octominin-treated group had a significantly higher relative percentage survival (54.1%) than the untreated group (16.6%). Additionally, a reduced bacterial load and fewer alterations in histological analysis confirmed the successful control of A. baumannii by Octominin in vivo. Collectively, these data suggest that Octominin exhibits significant antibacterial and antibiofilm activities against the multidrug-resistant A. baumannii, and this AMP can be developed further as a potent AMP for the control of antibiotic resistance. Full article

(This article belongs to the Special Issue Peptide Antimicrobial Agents)

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42 pages, 6540 KiB

Open AccessArticle

Biological and Physico-Chemical Characteristics of Arginine-Rich Peptide Gemini Surfactants with Lysine and Cystine Spacers

by Damian Neubauer, Maciej Jaśkiewicz, Marta Bauer, Agata Olejniczak-Kęder, Emilia Sikorska, Karol Sikora and Wojciech Kamysz

Int. J. Mol. Sci. 2021, 22(7), 3299; https://doi.org/10.3390/ijms22073299 - 24 Mar 2021

Cited by 12 | Viewed by 3760

Abstract

Ultrashort cationic lipopeptides (USCLs) and gemini cationic surfactants are classes of potent antimicrobials. Our recent study has shown that the branching and shortening of the fatty acids chains with the simultaneous addition of a hydrophobic N-terminal amino acid in USCLs result in compounds with enhanced selectivity. Here, this approach was introduced into arginine-rich gemini cationic surfactants. l-cystine diamide and l-lysine amide linkers were used as spacers. Antimicrobial activity against planktonic and biofilm cultures of ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) strains and Candida sp. as well as hemolytic and cytotoxic activities were examined. Moreover, antimicrobial activity in the presence of human serum and the ability to form micelles were evaluated. Membrane permeabilization study, serum stability assay, and molecular dynamics were performed. Generally, critical aggregation concentration was linearly correlated with hydrophobicity. Gemini surfactants were more active than the parent USCLs, and they turned out to be selective antimicrobial agents with relatively low hemolytic and cytotoxic activities. Geminis with the l-cystine diamide spacer seem to be less cytotoxic than their l-lysine amide counterparts, but they exhibited lower antibiofilm and antimicrobial activities in serum. In some cases, geminis with branched fatty acid chains and N-terminal hydrophobic amino acid resides exhibited enhanced selectivity to pathogens over human cells. Full article

(This article belongs to the Special Issue Peptide Antimicrobial Agents)

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14 pages, 3615 KiB

Open AccessArticle

The Neosartorya fischeri Antifungal Protein 2 (NFAP2): A New Potential Weapon against Multidrug-Resistant Candida auris Biofilms

by Renátó Kovács, Fruzsina Nagy, Zoltán Tóth, Lajos Forgács, Liliána Tóth, Györgyi Váradi, Gábor K. Tóth, Karina Vadászi, Andrew M. Borman, László Majoros and László Galgóczy

Int. J. Mol. Sci. 2021, 22(2), 771; https://doi.org/10.3390/ijms22020771 - 14 Jan 2021

Cited by 16 | Viewed by 2952

Abstract

Candida auris is a potential multidrug-resistant pathogen able to persist on indwelling devices as a biofilm, which serve as a source of catheter-associated infections. Neosartorya fischeri antifungal protein 2 (NFAP2) is a cysteine-rich, cationic protein with potent anti-Candida activity. We studied the in vitro activity of NFAP2 alone and in combination with fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin against C. auris biofilms. The nature of interactions was assessed utilizing the fractional inhibitory concentration index (FICI), a Bliss independence model, and LIVE/DEAD viability assay. NFAP2 exerted synergy with all tested antifungals with FICIs ranging between 0.312–0.5, 0.155–0.5, 0.037–0.375, 0.064–0.375, and 0.064–0.375 for fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin, respectively. These results were confirmed using a Bliss model, where NFAP2 produced 17.54 μM²%, 2.16 μM²%, 33.31 μM²%, 10.72 μM²%, and 111.19 μM²% cumulative synergy log volume in combination with fluconazole, amphotericin B, anidulafungin, caspofungin, and micafungin, respectively. In addition, biofilms exposed to echinocandins (32 mg/L) showed significant cell death in the presence of NFAP2 (128 mg/L). Our study shows that NFAP2 displays strong potential as a novel antifungal compound in alternative therapies to combat C. auris biofilms. Full article

(This article belongs to the Special Issue Peptide Antimicrobial Agents)

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21 pages, 3201 KiB

Open AccessArticle

Double-Headed Cationic Lipopeptides: An Emerging Class of Antimicrobials

by Izabela Małuch, Oktawian Stachurski, Paulina Kosikowska-Adamus, Marta Makowska, Marta Bauer, Dariusz Wyrzykowski, Aleksandra Hać, Wojciech Kamysz, Milena Deptuła, Michał Pikuła and Emilia Sikorska

Int. J. Mol. Sci. 2020, 21(23), 8944; https://doi.org/10.3390/ijms21238944 - 25 Nov 2020

Cited by 8 | Viewed by 2723

Abstract

Antimicrobial peptides (AMPs) constitute a promising tool in the development of novel therapeutic agents useful in a wide range of bacterial and fungal infections. Among the modifications improving pharmacokinetic and pharmacodynamic characteristics of natural AMPs, an important role is played by lipidation. This study focuses on the newly designed and synthesized lipopeptides containing multiple Lys residues or their shorter homologues with palmitic acid (C₁₆) attached to the side chain of a residue located in the center of the peptide sequence. The approach resulted in the development of lipopeptides representing a model of surfactants with two polar headgroups. The aim of this study is to explain how variations in the length of the peptide chain or the hydrocarbon side chain of an amino acid residue modified with C₁₆, affect biological functions of lipopeptides, their self-assembling propensity, and their mode of action. Full article

(This article belongs to the Special Issue Peptide Antimicrobial Agents)

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Review

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13 pages, 921 KiB

Open AccessReview

The Double-Edged Sword of Beta2-Microglobulin in Antibacterial Properties and Amyloid Fibril-Mediated Cytotoxicity

by Shean-Jaw Chiou, Huey-Jiun Ko, Chi-Ching Hwang and Yi-Ren Hong

Int. J. Mol. Sci. 2021, 22(12), 6330; https://doi.org/10.3390/ijms22126330 - 13 Jun 2021

Cited by 16 | Viewed by 5465

Abstract

Beta2-microglobulin (B2M) a key component of major histocompatibility complex class I molecules, which aid cytotoxic T-lymphocyte (CTL) immune response. However, the majority of studies of B2M have focused only on amyloid fibrils in pathogenesis to the neglect of its role of antimicrobial activity. Indeed, B2M also plays an important role in innate defense and does not only function as an adjuvant for CTL response. A previous study discovered that human aggregated B2M binds the surface protein structure in Streptococci, and a similar study revealed that sB2M-9, derived from native B2M, functions as an antibacterial chemokine that binds Staphylococcus aureus. An investigation of sB2M-9 exhibiting an early lymphocyte recruitment in the human respiratory epithelium with bacterial challenge may uncover previously unrecognized aspects of B2M in the body’s innate defense against Mycobactrium tuberculosis. B2M possesses antimicrobial activity that operates primarily under pH-dependent acidic conditions at which B2M and fragmented B2M may become a nucleus seed that triggers self-aggregation into distinct states, such as oligomers and amyloid fibrils. Modified B2M can act as an antimicrobial peptide (AMP) against a wide range of microbes. Specifically, these AMPs disrupt microbe membranes, a feature similar to that of amyloid fibril mediated cytotoxicity toward eukaryotes. This study investigated two similar but nonidentical effects of B2M: the physiological role of B2M, in which it potentially acts against microbes in innate defense and the role of B2M in amyloid fibrils, in which it disrupts the membrane of pathological cells. Moreover, we explored the pH-governing antibacterial activity of B2M and acidic pH mediated B2M amyloid fibrils underlying such cytotoxicity. Full article

(This article belongs to the Special Issue Peptide Antimicrobial Agents)

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