Caprine Bactenecins as Promising Tools for Developing New Antimicrobial and Antitumor Drugs

Копейкин, П. М.; Zharkova, Maria S.; Kolobov, A. A.; Smirnova, Maria; С, Сухарева М; Umnyakova, Ekaterina S.; Kokryakov, V. N.; Орлов, Д. С.; Milman, Boris L.; Balandin, Sergey V.; Panteleev, Pavel V.; Ovchinnikova, Tatiana V.; Komlev, A. S.; Tossi, Alessandro; Shamova, Olga

doi:10.3389/fcimb.2020.552905

Cited by 14 publications

(18 citation statements)

References 83 publications

(115 reference statements)

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“…PrAMPs are in the spotlight for the development of new antibiotics, but their narrow spectrum of activity may hinder their further progress toward clinical use [ 14 , 18 ]. Therefore, in recent years, great efforts have been made to expand the antimicrobial spectrum of PrAMPs by introducing sequence modification, residue substitution, or both [ 27 , 38 , 39 , 40 , 41 ]. In this study, we tested the effect of lipidation on the mammalian PrAMP Bac7(1-16) and demonstrated that the addition of a lipid chain to Bac7(1-16) greatly enhanced its antibacterial activity.…”

Section: Discussionmentioning

confidence: 99%

Effects of Lipidation on a Proline-Rich Antibacterial Peptide

Armas

Stasi

Mardirossian

et al. 2021

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

Effects of Lipidation on a Proline-Rich Antibacterial Peptide

Armas

Stasi

Mardirossian

et al. 2021

IJMS

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“…The impact of AgNP-PG1 and AgNP-Lyz conjugates on the metabolic activity of E. coli ML-35p was compared with the effects of their components -gelatinized AgNPs and free PG-1 or lysozyme. For comparison, we also tested the action of ionic silver, in the form of silver nitrate, and of an AMP, ChBac3.4, that uses both a membranolytic and an intracellular mechanism to kill bacteria (Shamova et al, 2009;Kopeikin et al, 2020; Figure 2). The bacterial species, growth phase, tested compound concentrations and overall conditions were the same as used in the membrane permeability assay.…”

Section: Dynamics Of the Inhibition Of Bacterial Cells Metabolismmentioning

confidence: 99%

Silver Nanoparticles Functionalized With Antimicrobial Polypeptides: Benefits and Possible Pitfalls of a Novel Anti-infective Tool

et al. 2021

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Silver nanoparticles (AgNPs) and antimicrobial peptides or proteins (AMPs/APs) are both considered as promising platforms for the development of novel therapeutic agents effective against the growing number of drug-resistant pathogens. The observed synergy of their antibacterial activity suggested the prospect of introducing antimicrobial peptides or small antimicrobial proteins into the gelatinized coating of AgNPs. Conjugates with protegrin-1, indolicidin, protamine, histones, and lysozyme were comparatively tested for their antibacterial properties and compared with unconjugated nanoparticles and antimicrobial polypeptides alone. Their toxic effects were similarly tested against both normal eukaryotic cells (human erythrocytes, peripheral blood mononuclear cells, neutrophils, and dermal fibroblasts) and tumor cells (human erythromyeloid leukemia K562 and human histiocytic lymphoma U937 cell lines). The AMPs/APs retained their ability to enhance the antibacterial activity of AgNPs against both Gram-positive and Gram-negative bacteria, including drug-resistant strains, when conjugated to the AgNP surface. The small, membranolytic protegrin-1 was the most efficient, suggesting that a short, rigid structure is not a limiting factor despite the constraints imposed by binding to the nanoparticle. Some of the conjugated AMPs/APs clearly affected the ability of nanoparticle to permeabilize the outer membrane of Escherichia coli, but none of the conjugated AgNPs acquired the capacity to permeabilize its cytoplasmic membrane, regardless of the membranolytic potency of the bound polypeptide. Low hemolytic activity was also found for all AgNP-AMP/AP conjugates, regardless of the hemolytic activity of the free polypeptides, making conjugation a promising strategy not only to enhance their antimicrobial potential but also to effectively reduce the toxicity of membranolytic AMPs. The observation that metabolic processes and O2 consumption in bacteria were efficiently inhibited by all forms of AgNPs is the most likely explanation for their rapid and bactericidal action. AMP-dependent properties in the activity pattern of various conjugates toward eukaryotic cells suggest that immunomodulatory, wound-healing, and other effects of the polypeptides are at least partially transferred to the nanoparticles, so that functionalization of AgNPs may have effects beyond just modulation of direct antibacterial activity. In addition, some conjugated nanoparticles are selectively toxic to tumor cells. However, caution is required as not all modulatory effects are necessarily beneficial to normal host cells.

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“…Novel ribosome inhibitors should be highly effective against a wide range of pathogens and also should have a mechanism of action different from those of known antibiotics to prevent the cross-resistance effects. One of the classes of the desired compounds, which in recent years attracted much attention from scientists, are proline-rich antimicrobial peptides (PrAMPs) [ 4 , 5 ]. Despite moderate amino acid sequence homology and different polypeptide chain length, PrAMPs bind to an overlapping site within the ribosomal exit tunnel and inhibit translation either by blocking the transition from the initiation to the elongation phase [ 6 , 7 ] or by preventing dissociation of the termination factors [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Proline-Rich Cathelicidin from the Alpaca Vicugna pacos with Potency to Combat Antibiotic-Resistant Bacteria: Mechanism of Action and the Functional Role of the C-Terminal Region

et al. 2022

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Over recent years, a growing number of bacterial species have become resistant to clinically relevant antibiotics. Proline-rich antimicrobial peptides (PrAMPs) having a potent antimicrobial activity and a negligible toxicity toward mammalian cells attract attention as new templates for the development of antibiotic drugs. Here, we mined genomes of all living Camelidae species and found a novel family of Bac7-like proline-rich cathelicidins which inhibited bacterial protein synthesis. The N-terminal region of a novel peptide from the alpaca Vicugna pacos named VicBac is responsible for inhibition of bacterial protein synthesis with an IC50 value of 0.5 µM in the E. coli cell-free system whereas the C-terminal region allows the peptide to penetrate bacterial membranes effectively. We also found that the full-length VicBac did not induce bacterial resistance after a two-week selection experiment, unlike the N-terminal truncated analog, which depended on the SbmA transport system. Both pro- and anti-inflammatory action of VicBac and its N-terminal truncated variant on various human cell types was found by multiplex immunoassay. The presence of the C-terminal tail in the natural VicBac does not provide for specific immune-modulatory effects in vitro but enhances the observed impact compared with the truncated analog. The pronounced antibacterial activity of VicBac, along with its moderate adverse effects on mammalian cells, make this molecule a promising scaffold for the development of peptide antibiotics.

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Caprine Bactenecins as Promising Tools for Developing New Antimicrobial and Antitumor Drugs

Cited by 14 publications

References 83 publications

Effects of Lipidation on a Proline-Rich Antibacterial Peptide

Effects of Lipidation on a Proline-Rich Antibacterial Peptide

Silver Nanoparticles Functionalized With Antimicrobial Polypeptides: Benefits and Possible Pitfalls of a Novel Anti-infective Tool

A Novel Proline-Rich Cathelicidin from the Alpaca Vicugna pacos with Potency to Combat Antibiotic-Resistant Bacteria: Mechanism of Action and the Functional Role of the C-Terminal Region

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