Enhancing Antibiotic-Resistant Bacterial Infection Therapy: Self-Assembling Gemini Quaternary Ammonium-Functionalized Peptide Nanoassemblies with Multiple Antibacterial Mechanisms

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

The rising threat of antimicrobial-resistant (AMR) infections highlights the urgent need for effective antimicrobial agents and therapies. Peptide-based nanomaterials are well-placed to meet this need. Here, we explore conjugation gemini quaternary ammonium compounds (GQAs) with designed short hexapeptides create cationic low cytotoxicity minimal resistance tendency. (WA)3GQA8C self-assembles into nanoparticles exhibits potent activity against drug-resistant pathogens enhanced stability. protects subcutaneous abscess infection rescues mice from acute peritonitis by reducing systemic bacterial burden alleviating organ damage, superior effects vancomycin. Notably, thoroughly disrupts membrane integrity akin peeling fruit induce disintegration, a feat inaccessible conventional antibiotics. Mechanistic studies suggest that targets phospholipids phosphatidylglycerol (PG), inducing PG deformation form fibrous or lamellar structures, which leads disruption membrane. Furthermore, interference in lipoprotein trafficking exacerbates damage integrity. also synergizes impairing protein synthesis function ribosome. These quaternized peptide nanoassemblies provide rational strategy designing peptide-based combat growing threats resistant bacteria.

Language: Английский

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ACE2 mediates tryptophan alleviation on diarrhea by repairing intestine barrier involved mTOR pathway

Cellular & Molecular Biology Letters, Journal Year: 2024, Volume and Issue: 29(1)

Published: June 14, 2024

Abstract The membrane-delimited receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme (ACE2), which is expressed in the intestine, collaborates with broad neutral amino acid transporter 1 (B 0 AT1). Tryptophan (Trp) transported into intestinal epithelial cells by ACE2 and B AT1. However, whether its binding protein AT1 are involved Trp-mediated alleviation of injury largely unknown. Here, we used weaned piglets IPEC-J2 as models found that ACE2/B alleviated lipopolysaccharide (LPS)-induced diarrhea promoted barrier recovery via transport Trp. levels aryl hydrocarbon (AhR) mechanistic target rapamycin (mTOR) pathways were altered ACE2. Dietary Trp supplementation LPS-treated revealed promoting expression, examination morphology damage to was repaired. Our study demonstrated accompanied mediated through repair mTOR pathway.

Language: Английский

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Quinolone-mediated metabolic cross-feeding develops aluminium tolerance in soil microbial consortia

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 22, 2024

Aluminium (Al)-tolerant beneficial bacteria confer resistance to Al toxicity crops in widely distributed acidic soils. However, the mechanism by which microbial consortia maintain tolerance under acid and stress remains unknown. Here, we demonstrate that a soil bacterial consortium composed of Rhodococcus erythropolis Pseudomonas aeruginosa exhibit greater than either bacterium alone. P. releases quorum sensing molecule 2-heptyl-1H-quinolin-4-one (HHQ), is efficiently degraded R. erythropolis. This degradation reduces population density limitations further enhances metabolic activity stress. Moreover, converts HHQ into tryptophan, promoting synthesis peptidoglycan, key component for cell wall stability, thereby improving study reveals cross-feeding maintains tolerance, offering insights designing synthetic sustain food security sustainable agriculture regions. The resistant aluminium unclear. authors show signaling molecular produced one member can server as nutritional resource other tolerant synthesis.

Language: Английский

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Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy

eLife, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 6, 2025

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due their heterogeneity and unclear pathogenic mechanisms. We describe a child neonatal-onset epilepsy, developmental of intermediate severity, G256W heterozygosity. Analyzing prior channel cryoelectron microscopy models revealed G256 as node an arch-shaped non-covalent bond network linking S5, the pore turret, ion path. Co-expression dominantly suppressed conduction by wild-type subunits heterologous cells. Ezogabine partly reversed this suppression. Kcnq2 G256W/+ mice have epilepsy leading premature deaths. Hippocampal CA1 pyramidal cells from brain slices showed hyperexcitability. cell KCNQ3 immunolabeling was significantly shifted axon initial segments neuronal somata. Despite normal mRNA levels, mouse protein levels were reduced about 50%. Our findings indicate that pathogenicity results multiplicative effects, including reductions intrinsic conduction, subcellular targeting, stability. These studies provide evidence for unexpected novel role turret introduce valid animal model encephalopathy. results, spanning structure behavior, may be broadly applicable because majority encephalopathy patients share near selectivity filter.

Language: Английский

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The Cation−π Interaction in Chemistry and Biology

Chemical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

The cation-π interaction is an important noncovalent binding force that impacts all areas of chemistry and biology. Extensive computational gas phase experimental studies have established the potential strength essential nature interaction. Previous reviews emphasized model systems a variety biological examples. This work includes discussion those but emphasizes other are perhaps less well appreciated. These include novel ability alkali metals in water; application to organic synthesis chemical biology; cooperative behaviors multiple interactions, including adhesive proteins from mussels similar organisms formation modulation biomolecular condensates (phase separation); interactions involved recognizing DNA/RNA.

Language: Английский

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No country for old antibiotics! Antimicrobial peptides (AMPs) as next-generation treatment for skin and soft tissue infection

International Journal of Pharmaceutics, Journal Year: 2023, Volume and Issue: 642, P. 123169 - 123169

Published: June 24, 2023

Language: Английский

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Enhancing the Antimicrobial Properties of Peptides through Cell-Penetrating Peptide Conjugation: A Comprehensive Assessment

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(23), P. 16723 - 16723

Published: Nov. 24, 2023

Combining antimicrobial peptides (AMPs) with cell-penetrating (CPPs) has shown promise in boosting potency, especially against Gram-negative bacteria. We examined the CPP-AMP interaction distinct bacterial types based on cell wall differences. Our investigation focused AMPs incorporating penetratin CPP and dihybrid containing both TAT protein fragments from human immunodeficiency virus Antennapedia peptide (Antp). Assessment of TAT-AMP, AMP-Antp, TAT-AMP-Antp revealed their potential Gram-positive strains (Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus). Peptides TAT-AMP AMP-Antp using an amyloidogenic AMP S1 ribosomal Thermus thermophilus, at concentrations ranging 3 to 12 μM, exhibited enhanced activity B. cereus. TAT-AMP-Antp, Pseudomonas aeruginosa, a concentration µM, demonstrated potent S. MRSA. Notably, effectively inhibited Escherichia coli (E. coli) growth displayed effects similar gentamicin after 15 h incubation. Peptide characteristics determined diverse strains. The study highlights intricate relationship between properties potential. Mechanisms action are closely tied attributes. fragment MRSA, P. aeruginosa. only Antp lower activity. None investigated cytotoxic or cytostatic either BT-474 cells skin fibroblasts. In conclusion, CPP-AMPs offer various strains, offering insights for targeted development.

Language: Английский

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Study of an arginine- and tryptophan-rich antimicrobial peptide in peri-implantitis

Frontiers in Bioengineering and Biotechnology, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 7, 2025

The combination of hydrophilic arginine residues and hydrophobic tryptophan is considered to be the first choice for designing short-chain antimicrobial peptides (AMPs) due their potent antibacterial activity. Based on this, we designed an arginine- tryptophan-rich short peptide, VR-12. Peri-implantitis a significant microbial inflammatory disorder characterized by inflammation soft tissues surrounding implant, which ultimately leads progressive resorption alveolar bone. This study found through experiments, wound healing promotion anti-inflammatory experiments that VR-12 inhibited killed planktonic peri-implantitis-associated bacteria, biofilm formation, disrupted mature biofilms. Additionally, exhibited good biocompatibility with RAW264.7 cells human gingival fibroblasts (HGFs) cells, promoting proliferation both cell types. Moreover, induced HGFs migration expression migration-related factors, thereby tissue healing. also acted lipopolysaccharide (LPS)-induced exerting excellent properties affecting secretion/expression inflammation-related factors/genes. Therefore, may option warding off treatmenting peri-implantitis.

Language: Английский

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Molecular aspects of cell-penetrating peptides: key amino acids, membrane partners, and non-covalent interactions

Comptes Rendus Chimie, Journal Year: 2025, Volume and Issue: 28(G1), P. 37 - 51

Published: Jan. 20, 2025

Since the early 1990s, there has been considerable interest in cell-penetrating peptides (CPPs) capable of transporting various types molecules cells. These CPPs are endowed with ability to cross cell membrane by endocytosis and other, as yet poorly understood, translocation pathways. Translocation involves interactions peptide plasma components before it can contact, disrupt, and/or reorganize lipid bilayer. The is complex terms molecular composition structure. It separates external environment from interior composed thousands different lipids, proteins, sulfated carbohydrates, all arranged a dynamic manner at length scales. Floating above bilayer, negatively charged proteoglycans other polysaccharides form viscous, anionic matrix layer surrounding animal cells, which have go through reach Even though thickness structure this glycocalyx extremely variable types, ubiquitously membranes. On side, mostly short (less than 30 amino acids), positively sequences. Some also primary or secondary amphipathic properties. Understanding CPP pathways requires interdisciplinary approaches physical chemistry biology for identifying key acids sequence components, between two involved steps process. In following synthetic review, we focus on these aspects. Depuis le début des années 1990, les pénétrant cellules (CPP) et capables de transporter divers molécules, suscitent l'intérêt. Ces sont en effet dotés propriétés franchissement la cellulaire par endocytose d'autres voies non encore comprises dites translocation. La implique du avec composants plasmique, avant qu'il ne puisse entrer perturber et/ou réorganiser bicouche lipidique. plasmique est complexe termes moléculaires. Cette interface séparant l'environnement extérieur l'intérieur cellule composée milliers lipides, protéines d'hydrates carbone sulfatés, tous disposés manière (et dynamique) trois dimensions sur plusieurs échelles longueur. Notamment, glycosaminoglycanes (GAGs) forment une couche matricielle visqueuse anionique entourant cellules, dans laquelle doivent diffuser jusqu'à Bien que l'épaisseur cette matrice soient extrêmement variables d'un type à l'autre, pénètrent tout cellule. Les généralement courtes séquences cationiques (<30 acides), certaines dotées amphiphiles primaires ou secondaires. compréhension pénétrants nécessite approches interdisciplinaires, chimie physique biologie cellulaire, afin d'identifier acides aminés clés peptidiques, membranaires impliqués processus. Dans revue synthétique qui suit, nous concentrerons ces

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Improving the Activity and Selectivity of a Scorpion-Derived Peptide, A3a, against Acinetobacter baumannii through Rational Design

ACS Omega, Journal Year: 2025, Volume and Issue: 10(5), P. 4699 - 4710

Published: Jan. 30, 2025

The rise in antimicrobial resistance has led to an increased desire understand how peptides (AMPs) can be better engineered kill antibiotic-resistant bacteria. Previously, we showed that C-terminal amidation of a peptide, identified scorpion Androctonus amoreuxi venom, its activity against both Gram-positive and -negative Here, incorporate all-atom molecular dynamics (MD) simulations rational design strategy create analogues A3a with greater therapeutic potential. We discover two novel AMPs which achieve potency against, selectivity toward, Acinetobacter baumannii ATCC 19606 but via distinct mechanisms are effective Galleria mellonella models A. burn wound infection. While CD spectroscopy indicates adopts α-helix conformation the presence Gram-negative bacterial plasma membrane, MD reveal it hairpin during initial binding. Three different strategies, designed stabilize this conformation, produce substantially outcomes. Deletion Ile6 Ile10 restricts conformational flexibility, characteristic A3a, membrane binding, prevents adoption steady state, abrogates antibacterial activity. In contrast, substitution arginine 7 lysine (A3a[R7K]) or isoleucine 14 tryptophan (A3a[I14W]) does not consistently affect peptide conformations. Both these new rapidly bactericidal toward A3a[R7K] also causes rapid permeabilization while for peptides, is greatest A3a[I14W]. Integration atomistic into multidisciplinary approach understanding mechanism action valuable tool interpreting effects strategies.

Language: Английский

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