Polymer-Ag Nanocomposites with Enhanced Antimicrobial Activity against Bacterial Infection

Herein, a nontoxic nanocomposite is synthesized by reduction of silver nitrate in the presence of a cationic polymer displaying strong antimicrobial activity against bacterial infection. These nanocomposites with a large concentration of positive charge promote their adsorption to bacterial membranes through electrostatic interaction. Moreover, the synthesized nanocomposites with polyvalent and synergistic antimicrobial effects can effectively kill both Gram-positive and Gram-negative bacteria without the emergence of bacterial resistance. Morphological changes obtained by transmission electron microscope observation show that these nanocomposites can cause leakage and chaos of intracellular contents. Analysis of the antimicrobial mechanism confirms that the lethal action of nanocomposites against the bacteria started with disruption of the bacterial membrane, subsequent cellular internalization of the nanoparticles, and inhibition of intracellular enzymatic activity. This novel antimicrobial material with good cytocompatibility promotes healing of infected wounds in diabetic rats, and has a promising future in the treatment of other infectious diseases

Functional Silver Nanoparticle as a Benign Antimicrobial Agent That Eradicates Antibiotic-Resistant Bacteria and Promotes Wound Healing

With the increased prevalence of antibiotic-resistant bacteria infections, there is a pressed need for innovative antimicrobial agent. Here, we report a benign ε-polylysine/silver nanoparticle nanocomposite (EPL-<i>g</i>-butyl@AgNPs) with polyvalent and synergistic antibacterial effects. EPL-<i>g</i>-butyl@AgNPs exhibited good stability in aqueous solution and effective antibacterial activity against both Gram-negative (<i>P. aeruginosa</i>) and Gram-positive (<i>S. aureus</i>) bacteria without emergence of bacterial resistance. Importantly, the nanocomposites eradicated the antibiotic-resistant bacteria without toxicity to mammalian cells. Analysis of the antibacterial mechanism confirmed that the nanocomposites adhered to the bacterial surface, irreversibly disrupted the membrane structure of the bacteria, subsequently penetrated cells, and effectively inhibited protein activity, which ultimately led to bacteria apoptosis. Notably, the nanocomposites modulated the relative level of CD3⁺ T cells and CD68⁺ macrophages and effectively promoted infected wound healing in diabetic rats. This work improves our understanding of the antibacterial mechanism of AgNPs-based nanocomposites and offers guidance to activity prediction and rational design of effective antimicrobial nanoparticles

Functional Silver Nanocomposites as Broad-Spectrum Antimicrobial and Biofilm-Disrupting Agents

Biofilms’ tolerance has become a serious clinical concern due to their formidable resistance to conventional antibiotics and prevalent virulence. Therefore, there is an urgent need to develop alternative antimicrobial agents to eradicate biofilms but avoid using antibiotics. Herein, we successfully developed polymer functional silver nanocomposites by reduction of silver nitrate in the presence of a biocompatible carbohydrate polymer and a membrane-disrupting cationic polymer. The nanocomposites presented effective antimicrobial activity against Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus and Bacillus amyloliquefaciens). Confocal laser scanning macroscopy imaging demonstrated that the nanocomposites could efficiently disperse and eradicate the mature biofilms formed by the above four bacterial strains. The introduction of carbohydrate polymers onto nanocomposites effectively improved the biocompatibility, and these nanocomposites induced no significant red blood cell hemolysis and cytotoxicity toward mammalian cells. More importantly, the nanocomposites were able to well eradicate the bacterial biofilms formed on the silicone implants in vivo. In conclusion, the nanocomposites as the broad-spectrum biofilm-disrupting agent are significant in the design of new strategies to eradicate biofilms on indwelling medical devices

Near-Infrared Light-Activated Thermosensitive Liposomes as Efficient Agents for Photothermal and Antibiotic Synergistic Therapy of Bacterial Biofilm

Biofilm is closely related to chronic infections and is difficult to eradicate. Development of effective therapy strategies to control biofilm infection is still challenging. Aiming at biofilm architecture, we designed and prepared near-infrared-activated thermosensitive liposomes with photothermal and antibiotic synergistic therapy capacity to eliminate Pseudomonas aeruginosa biofilm. The liposomes with positive charge and small size aided to enter the biofilm microchannels and locally released antibiotics in infection site. The liposomes could remain stable at 37 °C and release about 80% antibiotics over 45 °C. The biofilm dispersion rate was up to 80%, which was a 7- to 8-fold rise compared to excess antibiotic alone, indicating that the localized antibiotic release and photothermal co-therapy improved the antimicrobial efficiency. In vivo drug-loaded liposomes in treating P. aeruginosa-induced abscess exhibited an outstanding therapeutic effect. Furthermore, photothermal treatment could stimulate the expression of bcl2-associated athanogene 3 to prevent normal tissue from thermal damage. The near-infrared-activated nanoparticle carriers had the tremendous therapeutic potential to dramatically enhance the efficacy of antibiotics through thermos-triggered drug release and photothermal therapy

A Water-Soluble Galactose-Decorated Cationic Photodynamic Therapy Agent Based on BODIPY to Selectively Eliminate Biofilm

A multitude of serious chronic infections are involved in bacterial biofilms that are difficult to eradicate. Here, a water-soluble galactose-functionalized cationic 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based photodynamic therapy agent was synthesized for selectively eliminating the bacterial biofilm. These conjugates can capture bacteria to form aggregations through electrostatic interaction and then generate a large number of reactive oxygen species (ROS) under visible light irradiation to kill the bacteria without the emergence of bacterial resistance. Simultaneously, this agent could effectively inhibit and eradicate both Gram-positive and Gram-negative bacterial biofilms. The in-depth analysis of the antimicrobial mechanism confirmed that the conjugates can quickly bind on the bacterial surface, irreversibly disrupt the bacterial membrane, and distinctly inhibit intracellular enzyme activity, ultimately leading to the bacterial death. Importantly, these conjugates are highly selective toward bacterial cells over mammalian cells as well as no cytotoxicity to A549 cells and no discernible hemolytic activity. Collectively, this water-soluble galactose-decorated cationic BODIPY-based photodynamic therapy agent design provides promising insights for the development of therapy for antibiotic-resistant bacteria

Single Continuous Near-Infrared Laser-Triggered Photodynamic and Photothermal Ablation of Antibiotic-Resistant Bacteria Using Effective Targeted Copper Sulfide Nanoclusters

The emergence of antibiotic-resistant bacterial strains has made conventional antibiotic therapies less efficient. The development of a novel nanoantibiotic approach for efficiently ablating such bacterial infections is becoming crucial. Herein, a collection of poly­(5-(2-ethyl acrylate)-4-methylthiazole-<i>g</i>-butyl)/copper sulfide nanoclusters (PATA-C4@CuS) was synthesized for efficient capture and effective ablation of levofloxacin-resistant Gram-negative and Gram-positive bacteria upon tissue-penetrable near-infrared (NIR) laser irradiation. In this work, we took advantage of the excellent photothermal and photodynamic properties of copper sulfide nanoparticles (CuSNPs) upon NIR laser irradiation and thiazole derivative as a membrane-targeting cationic ligand toward bacteria. The conjugated nanoclusters could anchor the bacteria to trigger the bacterial aggregation quickly and efficiently kill them. These conjugated nanoclusters could significantly inhibit levofloxacin-resistant Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Bacillus amyloliquefaciens at 5.5 μg/mL under NIR laser irradiation (980 nm, 1.5 W cm^–2, 5 min), which suggested that the heat and reactive oxygen species (ROS) generated from the irradiated CuSNPs attached to bacteria were effective in eliminating and preventing the regrowth of the bacteria. Importantly, the conjugated nanoclusters could promote healing in bacteria-infected rat wounds without nonspecific damage to normal tissue. These findings highlight the promise of the highly versatile multifunctional nanoantibiotics in bacterial infection

An Acid-Triggered Degradable and Fluorescent Nanoscale Drug Delivery System with Enhanced Cytotoxicity to Cancer Cells

To reduce side-effects of anticancer drugs, development of nanocarriers with precise biological functions is a critical requirement. In this study, the multifunctional nanoparticles combining imaging and therapy for tumor-targeted delivery of hydrophobic anticancer drugs were prepared via self-assembly of amphiphilic copolymers obtained using RAFT polymerization, specifically, acid-labile ortho ester and galactose. First, boron-dipyrromethene dye-conjugated chain transfer agent provides fluorescent imaging capability for diagnostic application. Second, nanoparticles were stable under physiological conditions but degraded in acidic tumor microenvironment, leading to enhanced anticancer efficacy. Third, the application of biocompatible glycopolymers efficiently increased the target-to-background ratio through carbohydrate–protein interactions. Data from cell viability, cellular internalization, flow cytometry, biodistribution and anticancer efficacy tests showed that the drug-loaded nanoparticles were capable of inhibiting cancer cell proliferation with significantly enhanced capacity. Our newly developed multifunctional nanoparticles may thus facilitate the development of effective drug delivery systems for application in diagnosis and therapy of cancer

Structure–Activity Relationship of Membrane-Targeting Cationic Ligands on a Silver Nanoparticle Surface in an Antibiotic-Resistant Antibacterial and Antibiofilm Activity Assay

To explore the structure–activity relationship of membrane-targeting cationic ligands on a silver nanoparticle surface in an antibiotic-resistant antibacterial and antibiofilm activity assay, a series of functionalized silver nanocomposites were synthesized. Tuning the structural configuration, molecular weight, and side-chain length of the cationic ligands on the nanoparticle surface provided silver nanocomposites with effective antibacterial activity against both antibiotic-resistant Gram-negative and Gram-positive bacteria, including bacterial biofilms. These silver nanocomposites did not trigger hemolytic activity. Significantly, the bacteria did not develop resistance to the obtained nanocomposites even after 30 generations. A study of the antibacterial mechanism confirmed that these nanocomposites could irreversibly disrupt the membrane structure of bacteria and effectively inhibit intracellular enzyme activity, ultimately leading to bacterial death. The silver nanocomposites (64 μg/mL) could eradicate 80% of an established antibiotic-resistant bacterial biofilm. The strong structure–activity relationship toward antibacterial and antibiofilm activity suggests that variations in the conformational property of the functional ligand could be valuable in the discovery of new nano-antibacterial agents for treating pathogenic bacterial infections

Fig 2 -

Kaplan–Meier plot of cumulative incidence of remission of type 2 diabetes (A) and cumulative incidence of return to hyperglycaemia among people with diabetes remission (B) according to 1-year weight change (%) after diabetes diagnosis.</p

The absolute number of all-cause and selected cause-specific deaths attributable to risk factors by age in people with type 2 diabetes.

(DOCX)</p