Medical device-associated infections are a serious medical threat, particularly for patients with impaired mobility and/or advanced age. Despite a variety of antimicrobial coatings for medical devices being explored to date, only a limited number have been introduced for clinical use. Research into new bactericidal agents with the ability to eradicate pathogens, limit biofilm formation, and exhibit satisfactory biocompatibility, is therefore necessary and urgent. In this study, a series of varied-morphology gold nanoparticles in shapes of rods, peanuts, stars and spherical-like, porous ones with potent antibacterial activity were synthesized and thoroughly tested against spectrum of Candida albicans, Pseudomonas aeruginosa, Staphylococcus aureus clinical strains, as well as spectrum of uropathogenic Escherichia coli isolates. The optimization of gold nanoparticles synthesis allowed to develop nanomaterials, which are proved to be significantly more potent against tested microbes compared with the gold nanoformulations reported to date. Notably, their antimicrobial spectrum includes strains with different drug resistance mechanisms. Facile and cost-efficient synthesis of gold nanoparticles, remarkable bactericidal efficiency at nanogram doses, and low toxicity, underline their potential for development as a new coatings, as indicated by the example of urological catheters. The presented research fills a gap in microbial studies of non-spherical gold nanoparticles for the development of antimicrobial coatings targeting multidrug-resistant pathogens responsible for device-associated nosocomial infections.
Infection of human cells by pathogens, including SARS‐CoV‐2, typically proceeds by cell surface binding to a crucial receptor. The primary receptor for SARS‐CoV‐2 is the angiotensin‐converting enzyme 2 (ACE2), yet new studies reveal the importance of additional extracellular co‐receptors that mediate binding and host cell invasion by SARS‐CoV‐2. Vimentin is an intermediate filament protein that is increasingly recognized as being present on the extracellular surface of a subset of cell types, where it can bind to and facilitate pathogens’ cellular uptake. Biophysical and cell infection studies are done to determine whether vimentin might bind SARS‐CoV‐2 and facilitate its uptake. Dynamic light scattering shows that vimentin binds to pseudovirus coated with the SARS‐CoV‐2 spike protein, and antibodies against vimentin block in vitro SARS‐CoV‐2 pseudovirus infection of ACE2‐expressing cells. The results are consistent with a model in which extracellular vimentin acts as a co‐receptor for SARS‐CoV‐2 spike protein with a binding affinity less than that of the spike protein with ACE2. Extracellular vimentin may thus serve as a critical component of the SARS‐CoV‐2 spike protein‐ACE2 complex in mediating SARS‐CoV‐2 cell entry, and vimentin‐targeting agents may yield new therapeutic strategies for preventing and slowing SARS‐CoV‐2 infection.
Background and Purpose: Treatment of infections caused by NDM-1 carbapenemaseproducing Enterobacteriaceae (CPE) represents one of the major challenges of modern medicine. In order to address this issue, we tested ceragenins (CSAs-cationic steroid antimicrobials) as promising agents to eradicate various NDM-1-producing Gram-negative enteric rods. Materials and Methods: Susceptibility to CSA-13, CSA-44, and CSA-131 of four reference NDM-1 carbapenemase-producing strains, ie, Escherichia coli BAA-2471, Enterobacter cloacae BAA-2468, Klebsiella pneumoniae subsp. pneumoniae BAA-2472, and K. pneumoniae BAA-2473 was assessed by MIC/MBC testing of planktonic cells as well as biofilm formation/disruption assays. To define the mechanism of CSAs bactericidal activity, their ability to induce generation of reactive oxygen species (ROS), permeabilization of the inner and outer membranes, and their mechanical and adhesive properties upon CSA addition were examined. Additionally, hemolytic assays were performed to assess CSAs hemocompatibility. Results: All tested CSAs exert substantial bactericidal activity against NDM-1-producing bacteria. Moreover, CSAs significantly prevent biofilm formation as well as reduce the mass of developed biofilms. The mechanism of CSA action comprises both increased permeability of the outer and inner membrane, which is associated with an extensive ROS generation. Additionally, atomic force microscopy (AFM) analysis has shown morphological alterations in bacterial cells and the reduction of stiffness and adhesion properties. Importantly, CSAs are characterized by low hemolytic activity at concentrations that are bactericidal. Conclusion: Development of ceragenins should be viewed as one of the valid strategies to provide new treatment options against infections associated with CPE. The studies presented herein demonstrate that NDM-1-positive bacteria are more susceptible to ceragenins than to conventional antibiotics. In effect, CSA-13, CSA-44, and CSA-131 may be favorable for prevention and decrease of global burden of CPE.
Background Even with considerable improvement in treatment of epithelial ovarian cancer achieved in recent years, an increasing chemotherapy resistance and disease 5-year relapse is recorded for a majority part of patients that encourages the search for better therapeutic options. Gold nanoparticles (Au NPs) due to plethora of unique physiochemical features are thoroughly tested as drug delivery, radiosensitizers, as well as photothermal and photodynamic therapy agents. Importantly, due to highly controlled synthesis, it is possible to obtain nanomaterials with directed size and shape. Methods In this work, we developed novel elongated-type gold nanoparticles in the shape of nanopeanuts (AuP NPs) and investigated their cytotoxic potential against ovarian cancer cells SKOV-3 using colorimetric and fluorimetric methods, Western blot, flow cytometry, and fluorescence microscopy. Results Peanut-shaped gold nanoparticles showed high anti-cancer activity in vitro against SKOV-3 cells at doses of 1–5 ng/mL upon 72 hours treatment. We demonstrate that AuP NPs decrease the viability and proliferation capability of ovarian cancer cells by triggering cell apoptosis and autophagy, as evidenced by flow cytometry and Western blot analyses. The overproduction of reactive oxygen species (ROS) was noted to be a critical mediator of AuP NPs-mediated cell death. Conclusion These data indicate that gold nanopeanuts might be developed as nanotherapeutics against ovarian cancer.
In this work, we investigate whether stiffening in compression is a feature of single cells and whether the intracellular polymer networks that comprise the cytoskeleton (all of which stiffen with increasing shear strain) stiffen or soften when subjected to compressive strains. We find that individual cells, such as fibroblasts, stiffen at physiologically relevant compressive strains, but genetic ablation of vimentin diminishes this effect. Further, we show that unlike networks of purified F-actin or microtubules, which soften in compression, vimentin intermediate filament networks stiffen in both compression and extension, and we present a theoretical model to explain this response based on the flexibility of vimentin filaments and their surface charge, which resists volume changes of the network under compression. These results provide a new framework by which to understand the mechanical responses of cells and point to a central role of intermediate filaments in response to compression.
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