Multi-armed antibiotics for Gram-positive bacteria.

Antibiotic resistance is a serious threat to public health. Here, we propose a multi-armed chemical scaffold (MACS) for antibiotic screening, which refers to multi-armed molecules (MAMs) consisting of a core unit and three or four arms, neither of which is active for pathogens. Based on a structure-activity relationship study of MAMs, we discover a class of multi-armed antibiotics (MAAs) with a core similar to ethylene (E), carbon atom (C), benzene (B), nitrogen atom (N), and triazine (T) and three or four 4-phenylbenzoic acid (PBA) arms, or a B core and three 4-vinylbenzoic acid (VBA) or 4-ethynylbenzoic acid (EBA) arms. They can selectively interact with Gram-positive bacteria and inhibit cell wall assembly by targeting the lipid carriers of cell wall biosynthesis. MAAs have excellent antibacterial activities against Gram-positive bacteria, including clinical multi-drug-resistant (MDR) isolates. Our study provides a chemical scaffold and identifies eight antibacterial lead compounds for the development of antibiotics.

Gold nanoparticles bearing a clinically used non-antibiotic drug for combating multi-drug resistant bacteria.

We introduce N-acetyl-L-cysteine (NAC), a clinically used non-antibiotic drug, to the synthesis of antibacterial gold nanoparticles (Au_NAC). Au_NAC shows excellent antibacterial activities against multi-drug resistant (MDR) Gram-negative bacteria and possesses wound healing capabilities. We provide a new direction for antibiotic design and novel uses of known drugs.

Controlling the pyridinium-zwitterionic ligand ratio on atomically precise gold nanoclusters allowing for eradicating Gram-positive drug-resistant bacteria and retaining biocompatibility.

Infections caused by multidrug-resistant (MDR) bacteria are an increasing global healthcare concern. In this study, we developed a dual-ligand-functionalised Au25(SR1) x (SR2)18-x -type gold nanocluster and determined its antibacterial activity against MDR bacterial strains. The pyridinium ligand (SR1) provided bactericidal potency and the zwitterionic ligand (SR2) enhanced the stability and biocompatibility. By optimising the ligand ratio, our gold nanocluster could effectively kill MDR Gram-positive bacteria via multiple antibacterial actions, including inducing bacterial aggregation, disrupting bacterial membrane integrity and potential, and generating reactive oxygen species. Moreover, combining the optimised gold nanocluster with common antibiotics could significantly enhance the antibacterial activity against MDR bacteria both in in vitro and animal models of skin infections. Furthermore, the fluorescence of the gold nanocluster at the second near-infrared (NIR-II) biological window allowed for the monitoring of its biodistribution and body clearance, which confirmed that the gold nanoclusters had good renal clearance and biocompatibility. This study provides a new strategy to combat the MDR challenge using multifunctional gold nanomaterials.

Integrating a Concentration Gradient Generator and a Single-Cell Trapper Array for High-Throughput Screening the Bioeffects of Nanomaterials.

We herein develop a concentration gradient generator (CGG) on a microfluidic chip for diluting different nanoparticles. Specifically designed compact disk (CD)-shaped microchannels in the CGG module could thoroughly mix the flowing solutions and generate a linear concentration gradient of nanoparticles without aggregation. We combine the CGG with a single-cell trapper array (SCA) on microfluidics to evaluate the concentration-dependent bioeffects of the nanoparticles. The precise control of the spatiotemporal generation of nanoparticle concentration on the CGG module and the single-cell-level monitoring of the cell behaviors on the SCA module by a high-content system in real time, render the CGG-SCA system a highly precise platform, which can exclude the average effect of cell population and reflect the response of individual cells to the gradient concentrations accurately. In addition, the CGG-SCA system provides an automated platform for high-throughput screening of nanomedicines with high precision and low sample consumption.

The antibacterial activities of MoS2 nanosheets towards multi-drug resistant bacteria.

We demonstrated that molybdenum disulfide (MoS2) nanosheets can be an excellent solar disinfection agent for multi-drug resistant (MDR) bacteria with disinfection efficiencies >99.9999% in only 30 min. Distinct from other reactive oxygen species (ROS)-dependent photocatalysts, both ROS generation and size decrease contributed to the high antibacterial efficiencies of MoS2.

Reversing Bacterial Resistance to Gold Nanoparticles by Size Modulation.

One major frustration in developing antibiotics is that bacteria can quickly develop resistance that would require an entirely new cycle of research and clinical testing to overcome. Although plenty of bactericidal nanomaterials have been developed against increasingly severe superbugs, few reports have studied the resistance to these nanomaterials. Herein, we show that antibacterial 4,6-diamino-2-pyrimidine thiol (DAPT)-capped gold nanoparticles (AuDAPTs) can induce a 16-fold increased minimum inhibitory concentration (MIC) of E. coli only after very long term exposure (183 days), without developing cross-resistance to commercialized antibiotics. Strikingly, we recovered the bactericidal activities of AuDAPTs to the resistant strain by tuning the sizes of AuDAPTs without employing new chemicals. Such slow, easy-to-handle resistance induced by AuDAPTs is unprecedented compared to traditional antibiotics or other nanomaterials. In addition to the novel antibacterial activities and biocompatibilities, our approach will accelerate the development of gold nanomaterial-based therapeutics against multi-drug-resistant (MDR) bacterial infections.

Bimetallic nanoparticles against multi-drug resistant bacteria.

We discovered two antibacterial bimetallic nanoparticles (AuRh and AuRu NPs), that possess antibacterial activities against multi-drug resistant (MDR) Gram-negative bacteria and can cure wound infections. None of the nanoparticles comprising just one of these metals elements shows any antibiotic activities.

Four-in-One: Advanced Copper Nanocomposites for Multianalyte Assays and Multicoding Logic Gates.

The usage of non-noble-metal nanomaterials for nanoprobes or functional modules is still a big challenge because of their poor stability, functionality, and surface plasmon resonance property. In this work, copper ion, mercaptosuccinic acid, and nanocrystalline cellulose are combined for facile one-step synthesis and self-assembly of ultrasmall copper nanoparticles to produce supercolloidal particles (NCC@MSA-Cu SPs). Cu SPs show advanced multifunctionality for fast point-of-care tests (POCTs) of four metal ions (Hg2+, Pb2+, Ag+, and Zr4+). These selective recognitions integrate four different chemical reaction mechanisms (ion etching, core-shell deposition, templated synthesis, and precipitation) to produce four distinct readout signals. The multisignal mode-guided multianalyte sensing strategy can effectively avoid interference that affects single signal mode-based sensing. Benefiting from the creative multi-input and multireadout abilities, the visual multicoding logic gates of OR, NOR, AND, and INHIBIT are built based on optical responses of Cu SPs.

Indole Derivative-Capped Gold Nanoparticles as an Effective Bactericide in Vivo.

We synthesize indole derivative-capped gold nanoparticles (Au_IDs) via a straightforward route to fight multidrug-resistant (MDR) bacteria. When gold nanoparticles are modified with two indole derivatives, tryptophan and 5-aminoindole, they exhibit excellent antibacterial activities against both laboratory antibiotic-sensitive and MDR bacteria. Au_IDs possess remarkable bactericidal activities against MDR bacteria killing 99.9% of MDR Escherichia coli and polymyxin-resistant Klebsiella pneumoniae after 0.5 h of incubation, which are superior to clinical antibiotics including polymyxin B and cefotaxime. By evaluating the potential of Au_IDs in wound cure, Au_IDs show outstanding capability in MDR bacterial wound infection. Our findings provide new candidates for the development of bactericides and the fabrication of wound dressings for treating MDR infection.

Nanocatalyst Complex Can Dephosphorylate Key Proteins in MAPK Pathway for Cancer Therapy.

Controlling phosphorylation processes of proteins is a facile way for manipulating cell fates. Herein, a synergistic therapeutic strategy utilizing a near-infrared (NIR)-responsive nanocatalyst (NC) complex is presented, which is comprised of photoactive NC and protein phosphatase 2A (PP2A), to synergistically inhibit hyperphosphorylation of mitogen-activated protein kinase (MAPK) pathway for cancer therapy, as an example of many biological processes this approach can apply to. NIR-triggered release of PP2A specially dephosphorylates and inactivates mitogen-activated protein kinase kinase (MAP2K, also known as MEK) and extracellular regulated protein kinases (ERK) in the MAPK pathway, meanwhile, the NIR-triggered activation of NC decreases the level of intracellular adenosine triphosphate to attenuate protein phosphorylation of MEK and ERK. The synergistic therapeutics effectively suppress melanoma progression by inhibiting hyperphosphorylation of the MAPK pathway. In addition, the nanocatalyst complex reduces the risk of drug-resistance through inhibiting a rebound of RAS-GTP. The NIR-responsive nanocatalyst complex paves a novel way for cancer therapeutics.

Mixing-to-Answer Iodide Sensing with Commercial Chemicals.

We develop a convenient, colorimetric assay (Au/PEI) for rapid iodide (I-) determination that can be prepared facilely by mixing commercially available chemicals including tetrachloroauric acid (HAuCl4) and poly(ether imide) (PEI), and the assay can be carried out directly by adding the samples to the assay without any pretreatment and additional procedure. Au/PEI operates on the principle that I- accelerates the formation of Au NPs, which leads to a visible color change from light yellow to red for naked-eye readout with high specificity. We integrate our assay on solid devices including gel hybrids (Au/PEI/GH) and filter paper (Au/PEI paper) to satisfy the demand of point-of-care testing and justify the practicality by detecting I- in lake water that was supplemented with 10, 20, or 40 µM of I-. Au/PEI/GH with the limit of detection of 0.35 µM can satisfy the detection of drinking water based on the guidelines (1.2 µM) set by the Chinese government, and Au/PEI paper can be used even after 1 year of storage. Such assays provide a convenient and straightforward choice for routine, on-site I- tests.

Nanocrystalline cellulose mediated seed-growth for ultra-robust colorimetric detection of hydrogen sulfide.

We describe an ultra-stable, ultra-robust, straightforward and low-cost approach for the colorimetric detection of H2S with nanocrystalline cellulose (NCC) based on the reaction of H2S with lead acetate. The presence of NCC not only mediates the seed growth of a PbS/NCC complex, but also acts as a stabilizer protecting PbS from precipitation. This stable system is so robust that it can be used to quantitatively detect H2S even after two-year storage.

Universal Coating from Electrostatic Self-Assembly to Prevent Multidrug-Resistant Bacterial Colonization on Medical Devices and Solid Surfaces.

We provide a facile and scalable strategy for preparing gold nanoparticles (AuNPs)-based antibacterial coating on a variety of surfaces through electrostatic self-assembly. AuNPs conjugated with 4,6-diamino-2-pyrimidinethiol (DAPT, not antibacterial by itself), AuDAPT, can form stable coating on different substrates made from polyethylene (PS), polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE), polydimethylsiloxane (PDMS), and SiO2 in one step. Such a coating can efficiently eradicate pathogenic Gram-negative bacteria and even multidrug-resistant (MDR) mutants without causing any side-effect such as cytotoxicity, hemolysis, coagulation, and inflammation. We show that immobilized AuDAPT, instead of AuDAPT released from the substrate, is responsible for killing the bacteria and that the antimicrobial components do not enter into the environment to cause secondary contamination to breed drug resistance. Advantages for such coating include applicability on a broad range of surfaces, low cost, stability, high antibacterial efficiency, good biocompatibility, and low risk in antibiotics pollution; these advantages may be particularly helpful in preventing infections that involve medical devices.

Composites of Bacterial Cellulose and Small Molecule-Decorated Gold Nanoparticles for Treating Gram-Negative Bacteria-Infected Wounds.

Bacterial infections, especially multidrug-resistant bacterial infections, are an increasingly serious problem in the field of wound healing. Herein, bacterial cellulose (BC) decorated by 4,6-diamino-2-pyrimidinethiol (DAPT)-modified gold nanoparticles (Au-DAPT NPs) is presented as a dressing (BC-Au-DAPT nanocomposites) for treating bacterially infected wounds. BC-Au-DAPT nanocomposites have better efficacy (measured in terms of reduced minimum inhibition concentration) than most of the antibiotics (cefazolin/sulfamethoxazole) against Gram-negative bacteria, while maintaining excellent physicochemical properties including water uptake capability, mechanical strain, and biocompatibility. On Escherichia coli- or Pseudomonas aeruginosa-infected full-thickness skin wounds on rats, the BC-Au-DAPT nanocomposites inhibit bacterial growth and promote wound repair. Thus, the BC-Au-DAPT nanocomposite system is a promising platform for treating superbug-infected wounds.

Pharmaceutical Intermediate-Modified Gold Nanoparticles: Against Multidrug-Resistant Bacteria and Wound-Healing Application via an Electrospun Scaffold.

Remedying a multidrug-resistant (MDR) bacteria wound infection is a major challenge due to the inability of conventional antibiotics to treat such infections against MDR bacteria. Thus, developing wound dressings for wound care, particularly against MDR bacteria, is in huge demand. Here, we present a strategy in designing wound dressings: we use a small molecule (6-aminopenicillanic acid, APA)-coated gold nanoparticles (AuNPs) to inhibit MDR bacteria. We dope the AuNPs into electrospun fibers of poly(ε-caprolactone) (PCL)/gelatin to yield materials that guard against wound infection by MDR bacteria. We systematically evaluate the bactericidal activity of the AuNPs and wound-healing capability via the electrospun scaffold. APA-modified AuNPs (Au_APA) exhibit remarkable antibacterial activity even when confronted with MDR bacteria. Meanwhile, Au_APA has outstanding biocompatibility. Moreover, an in vivo bacteria-infected wound-healing experiment indicates that it has a striking ability to remedy a MDR bacteria wound infection. This wound scaffold can assist the wound care for bacterial infections.

N-Heterocyclic molecule-capped gold nanoparticles as effective antibiotics against multi-drug resistant bacteria.

We demonstrate that N-heterocyclic molecule-capped gold nanoparticles (Au NPs) have broad-spectrum antibacterial activity. Optimized antibacterial activity can be achieved by using different initial molar ratios (1 : 1 and 10 : 1) of N-heterocyclic prodrugs and the precursor of Au NPs (HAuCl4). This work opens up new avenues for antibiotics based on Au NPs.

Nanocrystalline Cellulose-Assisted Generation of Silver Nanoparticles for Nonenzymatic Glucose Detection and Antibacterial Agent.

Nanocrystalline cellulose (NCC) is a kind of natural biopolymers with merits of large surface area, high specific strength and unique optical properties. This report shows that NCC can serve as the substrate, allowing glucose to reduce Tollen's reagent to produce silver nanoparticles (AgNPs) at room temperature. The generation of AgNPs is affected by the factors such as the concentrations of silver ions, NCC and glucose, as well as the different reaction temperatures. The AgNPs with NCC are applied for the development of a visual, quantitative, nonenzymatic and high-sensitive assay for glucose detection in serum. This assay is also used for monitoring the concentration change of glucose in medium during cell culture. For the antibacterial activity, the minimal inhibitory concentration (MIC) of the generated AgNPs with NCC is much lower than that of commercial AgNPs, attributed to the good dispersion of AgNPs with the presence of NCC. As NCC exhibits unique advantages including green, stable, inexpensive, and abundant, the NCC-based generation of AgNPs may find promising applications in clinical diagnosis, environmental monitoring, and the control of bacteria.

In situ deposition of a personalized nanofibrous dressing via a handy electrospinning device for skin wound care.

Current strategies for wound care provide limited relief to millions of patients who suffer from burns, chronic skin ulcers or surgical-related wounds. The goal of this work is to develop an in situ deposition of a personalized nanofibrous dressing via a handy electrospinning (e-spinning) device and evaluate its properties related to skin wound care. MCM-41 type mesoporous silica nanoparticles decorated with silver nanoparticles (Ag-MSNs) were prepared by a facile and environmentally friendly approach, which possessed long-term antibacterial activity and low cytotoxicity. Poly-ε-caprolactone (PCL) incorporated with Ag-MSNs was successfully electrospun (e-spun) into nanofibrous membranes. These in situ e-spun nanofibrous membranes allowed the continuous release of Ag ions and showed broad-spectrum antimicrobial activity against two common types of pathogens, Staphylococcus aureus and Escherichia coli. In addition, the in vivo studies revealed that these antibacterial nanofibrous membranes could reduce the inflammatory response and accelerate wound healing in Wistar rats. The above results strongly demonstrate that such patient-specific dressings could be broadly applied in emergency medical transport, hospitals, clinics and at the patients' home in the near future.