An official website of the United States government
Abstract Each year, thousands of patients die from antimicrobial‐resistant bacterial infections that fail to respond to conventional antibiotic treatment. Antimicrobial polymers are a promising new method of combating antibiotic‐resistant bacterial infections. We have previously reported the synthesis of a series of narrow‐spectrum peptidomimetic antimicrobial polyurethanes that are effective against Gram‐negative bacteria, such asEscherichia coli; however, these polymers are not effective against Gram‐positive bacteria, such asStaphylococcus aureus. With the aim of understanding the correlation between chemical structure and antibacterial activity, we have subsequently developed three structural variants of these antimicrobial polyurethanes using post‐polymerization modification with decanoic acid and oleic acid. Our results show that such modifications converted the narrow‐spectrum antibacterial activity of these polymers into broad‐spectrum activity against Gram‐positive species such asS. aureus, however, also increasing their toxicity to mammalian cells. Mechanistic studies of bacterial membrane disruption illustrate the differences in antibacterial action between the various polymers. The results demonstrate the challenge of balancing antimicrobial activity and mammalian cell compatibility in the design of antimicrobial polymer compositions. © 2019 Society of Chemical Industry
more »
« less
Hydrophilic nanoparticles that kill bacteria while sparing mammalian cells reveal the antibiotic role of nanostructures
Abstract To dissect the antibiotic role of nanostructures from chemical moieties belligerent to both bacterial and mammalian cells, here we show the antimicrobial activity and cytotoxicity of nanoparticle-pinched polymer brushes (NPPBs) consisting of chemically inert silica nanospheres of systematically varied diameters covalently grafted with hydrophilic polymer brushes that are non-toxic and non-bactericidal. Assembly of the hydrophilic polymers into nanostructured NPPBs doesn’t alter their amicability with mammalian cells, but it incurs a transformation of their antimicrobial potential against bacteria, including clinical multidrug-resistant strains, that depends critically on the nanoparticle sizes. The acquired antimicrobial potency intensifies with small nanoparticles but subsides quickly with large ones. We identify a threshold size (d silica ~ 50 nm) only beneath which NPPBs remodel bacteria-mimicking membrane into 2D columnar phase, the epitome of membrane pore formation. This study illuminates nanoengineering as a viable approach to develop nanoantibiotics that kill bacteria upon contact yet remain nontoxic when engulfed by mammalian cells.
more »
« less
- Award ID(s):
- 1810767
- PAR ID:
- 10376987
- Date Published:
- Journal Name:
- Nature Communications
- Volume:
- 13
- Issue:
- 1
- ISSN:
- 2041-1723
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
The adhesion of nanoparticles to lipid vesicles causes curvature deformations to the membrane to an extent determined by the competition between the adhesive interaction and the membrane’s elasticity. These deformations can extend over length scales larger than the size of a nanoparticle, leading to an effective membrane-curvature-mediated interaction between nanoparticles. Nanoparticles with uniform surfaces tend to aggregate into unidimensionally close-packed clusters at moderate adhesion strengths and endocytose at high adhesion strengths. Here, we show that the suppression of close-packed clustering and endocytosis can be achieved by the surface modification of the nanoparticles into Janus particles where a moiety of their surface is grafted with polymers under a good solvent condition. The osmotic pressure of the polymer brushes prevents membrane wrapping of the nanoparticles’ moieties that are grafted with polymers, thus suppressing their endocytosis. Furthermore, a repulsion between polymer brushes belonging to two nearby nanoparticles destabilizes the dimerization of the nanoparticles over a wide range of values of the polymers’ molecular weight and grafting density. This surface modification of nanoparticles should allow for reliable, non-close-packed, and tunable self-assemblies of nanoparticles.more » « less
-
Nanomaterials acquire a biomolecular corona upon introduction to biological media, leading to biological transformations such as changes in protein function, unmasking of epitopes, and protein fibrilization. Ex vivo studies to investigate the effect of nanoparticles on protein–protein interactions are typically performed in buffer and are rarely measured quantitatively in live cells. Here, we measure the differential effect of silica nanoparticles on protein association in vitro vs. in mammalian cells. BtubA and BtubB are a pair of bacterial tubulin proteins identified inProsthecobacterstrains that self-assemble like eukaryotic tubulin, first into dimers and then into microtubules in vitro or in vivo. Förster resonance energy transfer labeling of each of the Btub monomers with a donor (mEGFP) and acceptor (mRuby3) fluorescent protein provides a quantitative tool to measure their binding interactions in the presence of unfunctionalized silica nanoparticles in buffer and in cells using fluorescence spectroscopy and microscopy. We show that silica nanoparticles enhance BtubAB dimerization in buffer due to protein corona formation. However, these nanoparticles have little effect on bacterial tubulin self-assembly in the complex mammalian cellular environment. Thus, the effect of nanomaterials on protein–protein interactions may not be readily translated from the test tube to the cell in the absence of particle surface functionalization that can enable targeted protein–nanoparticle interactions to withstand competitive binding in the nanoparticle corona from other biomolecules.more » « less
-
Ultrafiltration (UF) is a common technique used in wastewater treatments. However, the issue of membrane fouling in UF can greatly hinder the effectiveness of the treatments. This study demonstrated a low-fouling composite cellulose membrane system based on microfibrillated cellulose (MFC) and silica nanoparticle additives. The incorporation of ‘non-spherical’ silica nanoparticles was found to exhibit better structural integration in the membrane (i.e., minimal aggregation of silica nanoparticles in the membrane scaffold) as compared to spherical silica. The resulting composite membranes were tested for UF using local wastewater, where the best-performing membrane exhibited higher permeation flux than commercial polyvinylidene difluoride (PVDF) and polyether sulfone (PES) membranes while maintaining a high separation efficiency (~99.6%) and good flux recovery ratio (>90%). The analysis of the fouling behavior using different models suggested that the processes of cake layer formation and pore-constriction were probably two dominant fouling mechanisms, likely due to the presence of humic substances in wastewater. The demonstrated cellulose composite membrane system showed low-fouling and high restoration capability by a simple hydraulic cleaning method due to the super hydrophilic nature of the cellulose scaffold containing silica nanoparticles.more » « less
-
Background Nanoparticles (NPs) hold promise as alternatives to antibiotics in the fight against multi-drug-resistant bacteria. However, concerns about their cytotoxicity, particularly their effects on mammalian cells, must be thoroughly addressed to ensure therapeutic safety. Amphiphilic Janus NPs, which have segregated hydrophobic and polycationic ligands on two hemispheres, have previously been shown to exhibit potent antibacterial activity. Methods In this study, we evaluated the cytotoxicity of amphiphilic Janus NPs in immune and cancer cell lines. Cytotoxicity assays were performed to assess the effects of Janus NPs on cell viability and membrane integrity, with a particular focus on how internalization of the nanoparticles influenced cellular responses. Results The results revealed that both immune and cancer cells exhibited negligible cytotoxic effects when exposed to Janus NPs. However, phagocytic immune cells demonstrated greater susceptibility to membrane damage and viability loss, suggesting that internalization plays a significant role in nanoparticle-induced cytotoxicity. Conclusions Amphiphilic Janus NPs show great potential as highly effective antibacterial agents with minimal cytotoxicity. While immune cells may be more vulnerable to nanoparticle-induced damage due to their internalization capacity, these findings support the further investigation of Janus NPs for clinical applications.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s41467-021-27193-9
