Antibacterial Activity Affected by the Conformational Flexibility in Glycine–Lysine Based α-Helical Antimicrobial Peptides

Rončević, Tomislav; Vukičević, Damir; Ilić, Nada; Krce, Lucija; Gajski, Goran; Tonkić, Marija; Goić-Barišić, Ivana; Zoranić, Larisa; Sonavane, Yogesh; Benincasa, Monica; Juretić, Davor; Maravić, Ana; Tossi, Alessandro

doi:10.1021/acs.jmedchem.7b01831

Cited by 55 publications

(53 citation statements)

References 51 publications

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“…This process causes a series of physiological changes. The morphological abnormalities of bacteria after treatment with these peptides has been observed by a range of microscopic approaches . Broadly speaking, antimicrobial peptides are more effective against bacteria than small organic molecules because they quickly recognize the negatively charged surface of the bacterial membrane and attack the phospholipid layer.…”

Section: Resultsmentioning

confidence: 99%

Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

et al. 2019

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Phenol‐soluble modulins (PSMs) are a large family of cytolytic peptide toxins produced by Staphylococcus aureus. Based on their amino acid sequences, we have constructed a small library of cationic isoleucine‐rich peptides for antimicrobial evaluation. Relative to the parent PSMs, peptide zp3 (GIIAGIIIKIKK‐NH2) was found to possess greatly improved physicochemical properties (soluble in water) and antibacterial activity (MIC=8 μm for E. coli, B. subtilis, and C. freundii) while maintaining low hemolytic activity (<5 % at 256 μm) and cytotoxicity (HEK293 cells IC50>80 μm). We reasoned that the selective activity of zp3 toward bacterial cells is due to its amphiphilic nature and positive net charge. Moreover, it is difficult for bacteria to develop resistance against zp3. Through microscopic studies of E. coli, we demonstrated that zp3 can penetrate the bacterial membrane, thereby causing leakage of the bacterial cytoplasm. Our findings present a promising antimicrobial peptide lead, which has great potential for further chemical modification.

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Section: Resultsmentioning

confidence: 99%

Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

et al. 2019

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“…The evolutionary basis for such residue preferences is unknown; however, there are intriguing hypothetical possibilities. Given their propensity to allow conformational freedom that deforms α-helical structure in aqueous environments, it is conceivable that glycine and alanine may allow peptides to remain in relatively unstructured, inactive (e.g., nontoxic) conformations before interacting with the microbial target (38). A number of studies have demonstrated that αHDPs can be unstructured in aqueous environments, adopting their strong α-helical conformation only upon encountering hydrophobic lipid membrane environments characteristic of microorganisms (2,17,18,39,40).…”

Section: Discussionmentioning

confidence: 99%

Unifying structural signature of eukaryotic α-helical host defense peptides

Yount

Weaver

Lee

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Diversity of α-helical host defense peptides (αHDPs) contributes to immunity against a broad spectrum of pathogens via multiple functions. Thus, resolving common structure-function relationships among αHDPs is inherently difficult, even for artificial-intelligencebased methods that seek multifactorial trends rather than foundational principles. Here, bioinformatic and pattern recognition methods were applied to identify a unifying signature of eukaryotic αHDPs derived from amino acid sequence, biochemical, and threedimensional properties of known αHDPs. The signature formula contains a helical domain of 12 residues with a mean hydrophobic moment of 0.50 and favoring aliphatic over aromatic hydrophobes in 18-aa windows of peptides or proteins matching its semantic definition. The holistic α-core signature subsumes existing physicochemical properties of αHDPs, and converged strongly with predictions of an independent machine-learning-based classifier recognizing sequences inducing negative Gaussian curvature in target membranes. Queries using the α-core formula identified 93% of all annotated αHDPs in proteomic databases and retrieved all major αHDP families. Synthesis and antimicrobial assays confirmed efficacies of predicted sequences having no previously known antimicrobial activity. The unifying α-core signature establishes a foundational framework for discovering and understanding αHDPs encompassing diverse structural and mechanistic variations, and affords possibilities for deterministic design of antiinfectives.antimicrobial | host defense | antiinfective | amphipathic | bioinformatics A ntimicrobial host defense peptides (HDPs) are an evolutionarily ancient arm of host immunity that first arose in prokaryotes as a means to counter microbial competitors. Subsequently, such peptides evolved through adaptive radiation to exist in all classes of eukaryotes, where they continue to act in firstline defense against infection (1). Extensive studies have established that such peptides are not indiscriminant detergents, but rather have complex and multimodal mechanisms of action (2-4).As a group, α-helical HDPs (αHDPs) are among the most rapidly evolving molecules characterized to date. Moreover, genes encoding αHDPs are under strong positive selection, affording a high degree of mutational tolerance despite being limited by the biophysical constraints of an amphipathic helix (5-8). When compounded over an evolutionary timescale, this process has generated an exceptionally diverse repertoire of peptides capable of exerting multiple antimicrobial mechanisms. However, such diversity and context-dependent activity have also presented challenges to identifying common αHDP structure-activity relationships (SARs). While a number of groups have used computational or quantitative SAR (QSAR) methods, these efforts have largely focused on drug candidate optimization (9-12). As a result, other than charge or amphipathicity, resolving the unifying physicochemical requisites in three-dimensional space that confer antimicrobial ac...

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“…Multidrug-resistant clinical strains were obtained from the University Hospital Centre Split, Croatia. Their origin and antibiotic resistance phenotypes were described previously [37]. Antifungal activity was estimated against an environmental isolate of opportunistic pathogenic yeast Candida albicans and food isolates of food spoilage moulds Penicillium citrinum and Aspergillus niger.…”

Section: Bacterial Strainsmentioning

confidence: 99%

Biological Effects of Glucosinolate Degradation Products from Horseradish: A Horse that Wins the Race

et al. 2020

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Horseradish degradation products, mainly isothiocyanates (ITC) and nitriles, along with their precursors glucosinolates, were characterized by GC-MS and UHPLC-MS/MS, respectively. Volatiles from horseradish leaves and roots were isolated using microwave assisted-distillation (MAD), microwave hydrodiffusion and gravity (MHG) and hydrodistillation (HD). Allyl ITC was predominant in the leaves regardless of the isolation method while MAD, MHG, and HD of the roots resulted in different yields of allyl ITC, 2-phenylethyl ITC, and their nitriles. The antimicrobial potential of roots volatiles and their main compounds was assessed against sixteen emerging food spoilage and opportunistic pathogens. The MHG isolate was the most active, inhibiting bacteria at minimal inhibitory concentrations (MICs) from only 3.75 to 30 µg/mL, and fungi at MIC50 between <0.12 and 0.47 µg/mL. Cytotoxic activity of volatile isolates and their main compounds were tested against two human cancer cell lines using MTT assay after 72 h. The roots volatiles showed best cytotoxic activity (HD; IC50 = 2.62 μg/mL) against human lung A549 and human bladder T24 cancer cell lines (HD; IC50 = 0.57 μg/mL). Generally, 2-phenylethyl ITC, which was tested for its antimicrobial and cytotoxic activities along with two other major components allyl ITC and 3-phenylpropanenitrile, showed the best biological activities.

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Antibacterial Activity Affected by the Conformational Flexibility in Glycine–Lysine Based α-Helical Antimicrobial Peptides

Cited by 55 publications

References 51 publications

Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

Unifying structural signature of eukaryotic α-helical host defense peptides

Biological Effects of Glucosinolate Degradation Products from Horseradish: A Horse that Wins the Race

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