Lack Of Antibacterial Activity Research Articles

A novel 12-membered ring non-antibiotic macrolide EM982 attenuates cytokine production by inhibiting IKKβ and IκBα phosphorylation

Antimicrobial resistance poses a serious threat to human health worldwide and its incidence continues to increase owing to the overuse of antibiotics and other factors. Macrolide antibiotics such as erythromycin (EM) have immunomodulatory effects in addition to their antibacterial activity. Long-term, low-dose administration of macrolides has shown clinical benefits in treating the non-infectious inflammatory respiratory diseases. However, this practice may also increase the emergence of drug-resistant bacteria. In this study, we synthesized a series of EM derivatives, and screened them for two criteria: (i) lack of antibacterial activity and (ii) ability to suppress tumor necrosis factor-α (TNF-α) production in THP-1 cells stimulated with lipopolysaccharide. Among the 37 synthesized derivatives, we identified a novel 12-membered ring macrolide EM982 that lacked antibacterial activity against Staphylococcus aureus and suppressed the production of TNF-α and other cytokines. The effects of EM982 on Toll-like receptor 4 (TLR4) signaling were analyzed using a reporter assay and western blotting. The reporter assay showed that EM982 suppressed the activation of transcription factors, NF-κB and/or activator protein 1 (AP-1), in HEK293 cells expressing human TLR4. Western blotting showed that EM982 inhibited the phosphorylation of both IκB kinase (IKK) β and IκBα, which function upstream of NF-κB, whereas it did not affect the phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and c-Jun N-terminal kinase, which act upstream of AP-1. These results suggest that EM982 suppresses cytokine production by inhibiting phosphorylation of IKKβ and IκBα, resulting in the inactivation of NF-κB.

Effect of TEMPO-oxidized bacterial cellulose nanofibers stabilized Pickering emulsion of cinnamon essential oil on structure and properties of gelatin composite films

Pure gelatin film often exhibits high hydrophilicity and a lack of antibacterial activity, hindering its practical application in the field of food preservation. To address these issues, we incorporated 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-oxidized bacterial cellulose (TOBC) nanofibers stabilized cinnamon essential oil (CEO) Pickering emulsions into the gelatin matrix to develop active food packaging films. The study revealed that the good distribution of emulsion droplets in the film matrix. While with increasing Pickering emulsion proportion, the microstructures of composite films were more heterogeneous, showing some pores or cavities. In addition, the insertion of TOBC-stabilized CEO emulsions could improve the elongation at break (EAB), water-resistance, UV blocking ability, and antibacterial activity of film, but reduced its tensile strength (TS) and water vapor barrier properties (WVP). Notably, the film prepared with 4 % TOBC-stabilized CEO Pickering emulsion demonstrated enhanced preservation of strawberries. Overall, the as-prepared gelatin-based active composite films have considerable potential for food packaging.

An injectable collagen peptide-based hydrogel with desirable antibacterial, self-healing and wound-healing properties based on multiple-dynamic crosslinking

Conventional collagen-based hydrogels as wound dressing materials are usually lack of antibacterial activity and easily broken when encountering external forces. In this work, we developed a collagen peptide-based hydrogel as a wound dressing, which was composed of adipic acid dihydrazide functionalized collagen peptide (Col-ADH), oxidized dextran (ODex), polyvinyl alcohol (PVA) and borax via multiple-dynamic reversible bonds (acylhydrazone, amine, borate ester and hydrogen bonds). The injectable hydrogel exhibited satisfactory self-healing ability, antibacterial activity, mechanical strength, as well as good biocompatibility and biodegradability. In vivo experiments demonstrated the rapid hemostasis, accelerated cell migration, and promoted wound healing capacities of the hydrogel. These results indicate that the multifunctional collagen peptide-based hydrogel has great potentials in the field of wound dressings.

Transparent silk fibroin film-facilitated infected-wound healing through antibacterial, improved fibroblast adhesion and immune modulation.

The clinical application of regenerated silk fibroin (RSF) films for wound treatment is restricted by its undesirable mechanical properties and lack of antibacterial activity. Herein, different pluronic polymers were introduced to optimize their mechanical properties and the RSF film with 2.5% pluronic F127 (RSFPF127) stood out to address the above issues owing to its satisfactory mechanical properties, hydrophilicity, and transmittance. Diverse antibacterial agents (curcumin, Ag nanoparticles, and antimicrobial peptide KR-12) were separately encapsulated in RSFPF127 to endow it with antibacterial activity. In vitro experiments revealed that the medicated RSFPF127 could persistently release drugs and had desirable bioactivities toward killing bacteria, promoting fibroblast adhesion, and modulating macrophage polarization. In vivo experiments revealed that medicated RSFPF127 not only eradicated methicillin-resistant Staphylococcus aureus in the wound area and inhibited inflammatory responses, but also facilitated angiogenesis and re-epithelialization, regardless of the types of antibacterial agents, thus accelerating the recovery of infected wounds. These results demonstrate that RSFPF127 is an ideal matrix platform to load different types of drugs for application as wound dressings.

Preparation and characterization of porous membranes of glucomannan and silver decorated cellulose nanocrystals for application as biomaterial

Bacterial infection usually represents a threat in medical wound care, due to the increase in treatment complexity and the risk of antibiotic resistance. For presenting interesting characteristics for the use as biomaterial, natural polymers have been explored for this application. Among them, a promising candidate is the konjac glucomannan (KGM) with outstanding biocompatibility and biodegradability but lack of antibacterial activity. In this study, KGM was combined with silver decorated cellulose nanocrystals (CNC-Ag) to prepare membranes by using a recent reported casting-freezing method. The results highlight the potential anti-adhesive activity of the new materials against Staphylococcus aureus upon contact, without the burst release of silver nanoparticles. Furthermore, the incorporation of CNC enhanced the thermal stability of these membranes while preserving the favorable mechanical properties of the KGM-based material. These findings highlight a straightforward approach to enhance the antibacterial properties of natural polymers, which can be effectively useful in medical devices like wound dressings that typically lack such properties.

Antibacterial and osteoconductive polycaprolactone/polylactic acid/nano-hydroxyapatite/Cu@ZIF-8 GBR membrane with asymmetric porous structure

Repair of periodontal and maxillofacial bone defects is a major challenge in clinical. Guided bone regeneration (GBR) is considered one of the most effective methods. However, the efficacy of currently available GBR membranes for repair is frequently limited by their poor osteogenic potential and lack of antibacterial activity. The first step in this investigation was to construct a zinc-based zeolite-imidazolate framework loaded with copper ions (Cu@ZIF-8). Following that, a novel polycaprolactone/polylactic acid/nano-hydroxyapatite/Cu@ZIF-8 (PCL/PLA/n-HA/Cu@ZIF-8) GBR membrane was developed using a simple porogen with nonsolvent-induced phase separation (NIPS) approach. The produced membrane with asymmetric porous structure (one smooth side and one rough side) possesses hydrophilicity corresponding to the roughness of its two sides. The superior mechanical property, stability of degradation, and ion release capability of the membrane all contribute to the clinical feasibility. Additionally, in vitro biological experiments demonstrated that the PCL/PLA/n-HA/Cu@ZIF-8 membrane had favorable osteogenic and antibacterial properties, which suggests the high potential for application in the GBR procedure.

PMMA-Based Nanocomposites for Odontology Applications: A State-of-the-Art.

Polymethyl methacrylate (PMMA), a well-known polymer of the methacrylate family, is extensively used in biomedicine, particularly in odontological applications including artificial teeth, dentures and denture bases, obturators, provisional or permanent crowns, and so forth. The exceptional PMMA properties, including aesthetics, inexpensiveness, simple manipulation, low density, and adjustable mechanical properties, make it a perfect candidate in the field of dentistry. However, it presents some deficiencies, including weakness regarding hydrolytic degradation, poor fracture toughness, and a lack of antibacterial activity. To further enhance its properties and solve these drawbacks, different approaches can be performed, including the incorporation of nanofillers. In this regard, different types of metallic nanoparticles, metal oxide nanofillers, and carbon-based nanomaterials have been recently integrated into PMMA matrices with the aim to reduce water absorption and improve their performance, namely their thermal and flexural properties. In this review, recent studies regarding the development of PMMA-based nanocomposites for odontology applications are summarized and future perspectives are highlighted.

Effect of plant tannin and glycerol on thermoplastic starch: Mechanical, structural, antimicrobial and biodegradable properties

Thermoplastic starch is a good candidate for preparing biobased plastics. However, certain deficiencies in the ingredient, such as its poor mechanical strength and lack of antibacterial activity, need to be strengthened. In this work, a new method of producing TPS via extrusion and injection at a large scale was explored using tannin and glycerol simultaneously. The effect of the tannin content on the performance of TPS was investigated. The results showed that the synergistic effect of a small amount of tannin (2.5–7.5 wt%) and glycerol increased the tensile strength and maintained a stable elongation at break, and tannin aggregation occurred in TPS at higher tannin contents, which corresponded to increased tensile and flexural strengths. 15T-TPS has optimal mechanical performance with maximal relative crystallinity. The introduced tannin in TPS effectively enhanced the thermal stability but slightly reduced the biodegradability in soil and endowed TPS with antibacterial activity. Therefore, TPS containing tannins has the potential to be used in biomedical, food packaging and agricultural areas.

Electrohydrodynamic Fabrication of Triple-layered Polycaprolactone Dura Mater Substitute with Antibacterial and Enhanced Osteogenic Capability

In the field of dura mater repair, it is essential to employ artificial substitutes mimicking the multilayered microarchitecture and multiple functions of native dura mater for effective neurosurgery. However, existing artificial dura mater substitutes commonly cause complications because of mismatched structural and mechanical properties as well as the lack of antibacterial activity or osteogenic capability. In this study, a triple-layered dura mater substitute was fabricated by electrohydrodynamic (EHD) jetting techniques, including electrospinning and melt-based EHD printing processes. Highly aligned polycaprolactone (PCL) nanofibers loaded with gentamicin sulfate (GS) were prepared by electrospinning to form the inner layer, which can mimic the aligned collagen fibers of the native dura mater. Random PCL-GS nanofibers were then deposited by electrospinning to form the middle layer. They were intended to enhance the mechanical properties of the fabricated scaffolds. The outer layer involving PCL microfibers doped with nano-hydroxyapatite (nHA) at various angles was printed by the melting-based EHD method, which can enhance osteogenic capability and promote the fusion between the dura mater substitute and the skull. The tensile strength of the triple-layered drug-loaded biomimetic dura mater substitute was 22.42 ± 0.89 MPa, and the elongation at break was 36.43% ± 2.00%. The addition of GS endowed the substitutes with an anti-infection property without influencing their cytocompatibility. Furthermore, the incorporation of nHA promoted the osteogenic differentiation of MC3T3-E1 cells seeded on the triple-layered scaffolds. This work offers a promising strategy to manufacture multilayered dura mater substitutes with the desired antibacterial and enhanced osteogenic capability performance, possibly providing a novel candidate for dural tissue repair.

BDDE-Inspired Chalcone Derivatives to Fight Bacterial and Fungal Infections.

The growing number of infectious diseases around the world threatens the effective response of antibiotics, contributing to the increase in antibiotic resistance seen as a global health problem. Currently, one of the main challenges in antimicrobial drug discovery is the search for new compounds that not only exhibit antimicrobial activity, but can also potentiate the antimicrobial activity and revert antibiotics’ resistance, through the interference with several mechanisms, including the inhibition of efflux pumps (EPs) and biofilm formation. Inspired by macroalgae brominated bromophenol BDDE with antimicrobial activity, a series of 18 chalcone derivatives, including seven chalcones (9–15), six dihydrochalcones (16–18, and 22–24) and five diarylpropanes (19–21, and 25 and 26), was prepared and evaluated for its antimicrobial activity and potential to fight antibiotic resistance. Among them, chalcones 13 and 14 showed promising antifungal activity against the dermatophyte clinical strain of Trichophyton rubrum, and all compounds reversed the resistance to vancomycin in Enterococcus faecalis B3/101, with 9, 14, and 24 able to cause a four-fold decrease in the MIC of vancomycin against this strain. Compounds 17–24 displayed inhibition of EPs and the formation of biofilm by S. aureus 272123, suggesting that these compounds are inhibiting the EPs responsible for the extrusion of molecules involved in biofilm-related mechanisms. Interestingly, compounds 17–24 did not show cytotoxicity in mouse embryonic fibroblast cell lines (NIH/3T3). Overall, the results obtained suggest the potential of dihydrochalcones 16–18 and 22–24, and diarylpropanes 19–21, 25 and 26, as hits for bacterial EPs inhibition, as they are effective in the inhibition of EPs, but present other features that are important in this matter, such as the lack of antibacterial activity and cytotoxicity.

Self-assembled NIR-responsive MoS2@quaternized chitosan/nanocellulose composite paper for recyclable antibacteria

Paper products are widely used in daily life, while the lack of antibacterial activity has made them become some disease transmission media. Herein, we introduced NIR-responsive molybdenum disulfide nanosheets (MoS2) to endow nanocellulose paper antibacterial activity by electrostatic self-assembly with quaternized chitosan (QCS). Firstly, the MoS2 nanosheets were exfoliated and stabilized with QCS under ultrasonication. The strong coordination between QCS and MoS2 as well as the electrostatic attraction between QCS and cellulose nanofiber (CNF) helped to fabricate the MoS2@QCS/CNF composite paper. The MoS2@QCS/CNF composite paper exhibited excellent photothermal and photodynamic activity, achieving over 99.9% antibacterial efficacy against both E. coli and S. aureus, respectively. The hyperthermia induced by MoS2 accelerated the glutathione (GSH) consumption and the reactive oxygen species (ROS)-independent oxidative stress destroyed the bacteria membranes integrity, synergistically leading to the malondialdehyde (MDA) oxidation and protein leakage to inhibit the bacteria growth. Importantly, the self-assembled fibrous network incorporating with the photo-stable antibacterial MoS2 enabled the flexible composite paper with excellent mechanical strength and recyclability for long-term antimicrobial, possessing over 99.9% inhibition even after five cycles. No cell cytotoxicity was observed for the MoS2@QCS/CNF composite paper, suggesting the potential of composite paper for bacterial infection control.

Chemical composition, cytotoxic effects, antimicrobial and antibiofilm activity of Artemisia arborescens (Vaill.) L. growing wild in the province of Agrigento, Sicily, Italy

Artemisia arborescens (Vaill.) L. is a perennial shrubby plant growing along the coastal strips of the Mediterranean region. It is used in traditional medicine. Its essential oil and solvent extracts exhibit a very interesting chemotherapeutic potential, which makes this plant useful in maintaining human health. The goal of this study was to determine the phytochemical composition of the petroleum ether and methanol extracts, as well as to evaluate anticancer activities and antimicrobial and biofilm formation reduction. Thirty-nine phytochemical compounds in negative ion mode and 25 in positive ion mode were identified by HPLC-ESI-QTOF-MS. All four extracts reduced the viability of human MDA-MB231 and HCT116 cancer cells suggesting a similar cytotoxic efficacy of the different extracts in MDA-MB231 and more pronounced antiproliferative effects on HCT116 cells treated with HPEE and CPEE. Antimicrobial activity was exhibited by the hot petroleum ether extract against all tested bacteria (MIC 0.15–2.5 mg/mL), except for S. agalactiae. Both methanol extracts showed activity against C. albicans with a MIC value of 2.5 mg/mL, and a lack of antibacterial activity. To whom concern the anti-biofilm activity, hot methanol extract shows the highest activity in inhibiting biofilm formation among all extract.

65. In Vivo Efficacy of Human Simulated Minocycline (MIN) against Stenotrophomonas maltophilia (STM)

BackgroundThe current susceptibility breakpoint for MIN against STM is 4mg/L, yielding >99% of isolates susceptible. Unfortunately, there are limited pre-clinical and clinical data to support this breakpoint for STM. The purpose of this study was to evaluate the efficacy of a MIN human simulated regimen (HSR) against STM across a wide range of MICs in the murine neutropenic thigh model.MethodsClinical STM with modal MIN MICS of 0.25-8mg/L were included. Confirmatory pharmacokinetic (PK) studies were performed in infected neutropenic mice to develop a MIN HSR providing an area under the curve (AUC) and maximum concentration (Cmax) exposure similar to MIN 100mg intravenous (IV) q12h at steady-state based on PK parameters from critically ill adult patients. The murine neutropenic thigh infection model was utilized to examine the antibacterial effects of the confirmed MIN HSR against 17 STM. Both thighs of neutropenic ICR mice were inoculated with bacterial suspensions of 107 colony forming units (CFU)/mL. Two hours after inoculation, the MIN HSR was administered subcutaneously (SC) over 24h. Control mice received normal saline. Efficacy was measured as the change in log10CFU/thigh at 24h compared with 0h controls.ResultsMIN 22, 10, 14, and 10mg/kg dosed SC at 0, 6, 12, and 18h best recapitulated the human Cmax and AUC profile. Mean ± standard deviation bacterial burden at 0h across all isolates was 6.03±0.32 log10CFU/thigh. Bacterial growth was 1.35±0.68 log10CFU/thigh in 24h controls. Six of 7 isolates (86%) with MIC ≤ 0.5mg/L achieved 1-log kill with MIN HSR (-1.44±1.37 log10CFU/thigh). All STM with MIC ≥ 1mg/L experienced bacterial growth (1.18±0.79 log10CFU/thigh) (Figure).Figure. Efficacy of a minocycline human simulated exposure of 100mg intravenous Q12h in the murine neutropenic thigh model against 17 clinical Stenotrophomonas maltophilia isolates ConclusionThese data describe the in vivo efficacy of a MIN HSR with exposures similar to MIN 100mg IV q12h in critically ill adults. Lack of antibacterial activity against STM with MICs ≥ 1mg/L justifies a reassessment of the current susceptibility breakpoint. The study was funded under FDA Contract 75F40120C00171. Disclosures David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)BioMérieux (Consultant, Research Grant or Support, Speaker’s Bureau)Contrafect (Scientific Research Study Investigator)GSK (Consultant)Merck (Research Grant or Support)Paratek (Speaker’s Bureau)Roche Diagnostics (Research Grant or Support)Shionogi (Research Grant or Support)Summit (Scientific Research Study Investigator)

Maximum levels of cross-contamination for 24 antimicrobial active substances in non-target feed. Part 3: Amprolium.

The specific concentrations of amprolium in non‐target feed for food‐producing animals, below which there would not be an effect on the emergence of, and/or selection for, resistance in bacteria relevant for human and animal health, as well as the specific antimicrobial concentrations in feed which have an effect in terms of growth promotion/increased yield were assessed by EFSA in collaboration with EMA. Details of the methodology used for this assessment, associated data gaps and uncertainties, are presented in a separate document. To address antimicrobial resistance, the Feed Antimicrobial Resistance Selection Concentration (FARSC) model developed specifically for the assessment was applied. However, due to the lack of data on the parameters required to calculate the FARSC for amprolium, it was not possible to conclude the assessment. To address growth promotion, data from scientific publications obtained from an extensive literature review were used. Levels of amprolium in feed that showed to have an effect on growth promotion/increased yield were reported. The lack of antibacterial activity at clinically relevant concentrations for amprolium suggests that further studies relating to bacterial resistance are not a priority.

Functionalization of Aminoalkylsilane-Grafted Bacterial Nanocellulose with ZnO-NPs-Doped Pullulan Electrospun Nanofibers for Multifunctional Wound Dressing.

High moisture permeability, excellent mechanical properties in a wet state, high water-holding capability, and high exudate absorption make bacterial nanocellulose (BNC) a favorable candidate for biomedical device production, especially wound dressings. The lack of antibacterial activity and healing-promoting ability are the main drawbacks that limit its wide application. Pullulan (Pul) is a nontoxic polymer that can promote wound healing. Zinc oxide nanoparticles (ZnO-NPs) are well-known as a safe antibacterial agent. In this study, aminoalkylsilane was chemically grafted on a BNC membrane (A-g-BNC) and used as a bridge to combine BNC with Pul-ZnO-NPs hybrid electrospun nanofibers. FTIR results confirmed the successful production of A-g-BNC/Pul-ZnO. The obtained dressing demonstrated blood clotting performance better than that of BNC. The dressing showed an ability to release ZnO, and its antibacterial activity was up to 5 log values higher than that of BNC. The cytotoxicity of the dressing toward L929 fibroblast cells clearly showed safety due to the proliferation of fibroblast cells. The animal test in a rat model indicated faster healing and re-epithelialization, small blood vessel formation, and collagen synthesis in the wounds covered by A-g-BNC/Pul-ZnO. The new functional dressing, fabricated with a cost-effective and easy method, not only showed excellent antibacterial activity but could also accelerate wound healing.

Effect of Graphene Oxide on the Properties of Poly(3-Hydroxybutyrate-co-3-Hydroxyhexanoate).

The main shortcomings of polyhydroxybutyrate (PHB), which is a biodegradable and biocompatible polymer used for biomedical and food packaging applications, are its low thermal stability, poor impact resistance and lack of antibacterial activity. This issue can be improved by blending with other biodegradable polymers such as polyhydroxyhexanoate to form poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx), which is a copolymer with better impact strength and lower melting point. However, PHBHHx shows reduced stiffness than PHB and poorer barrier properties against moisture and gases, which is a drawback for use in the food industry. In this regard, novel biodegradable PHBHHx/graphene oxide (GO) nanocomposites have been prepared via a simple, cheap and environmentally friendly solvent casting method to enhance the mechanical properties and antimicrobial activity. The morphology, mechanical, thermal, barrier and antibacterial properties of the nanocomposites were assessed via several characterization methods to show the enhancement in the biopolymer properties. The stiffness and strength of the biopolymer were enhanced up to 40% and 28%, respectively, related to the strong matrix-nanofiller interfacial adhesion attained via hydrogen bonding interactions. Moreover, the nanocomposites showed superior thermal stability (as far as 40 °C), lower water uptake (up to 70%) and better gas and vapour barrier properties (about 45 and 35% reduction) than neat PHBHHx. They also displayed strong biocide action against Gram positive and Gram negative bacteria. These bio-based nanocomposites with antimicrobial activity offer new perspectives for the replacement of traditional petroleum-based synthetic polymers currently used for food packaging.

A tough, adhesive, self-healable, and antibacterial plant-inspired hydrogel based on pyrogallol-borax dynamic cross-linking.

Multifunctional hydrogels that integrate stretchability, adhesion, self-healing, and antibacterial properties may find use in a variety of fields including electronic skin, wound dressings, and wearable devices; however, traditional hydrogels often exhibit short-term adhesiveness, poor mechanical properties, and a lack of antibacterial activity. Herein, a plant-inspired polyacrylamide-soybean protein isolate-pyrogallol/borax (PAM-SPI-P/B) hydrogel has been developed using a facile green method based on dynamic coordination cross-linking between pyrogallol (PG) and borax. The PG-borax dynamic bonds adjusted the network structure of the hydrogels to provide greater structural integrity to the PAM-SPI double network. This hydrogel possessed a high mechanical strength (large elongation up to 760% and compressive strength up to 1.25 MPa at 80% strain), low swelling ratio, and self-healing properties. Inspired by natural polyphenols that contain adhesive molecules, the addition of pyrogallol provided the hydrogel excellent adhesion to various hydrophilic and hydrophobic substrates. And with the inhibition of pyrogallol autoxidation due to the borax protection, the hydrogel showed repeatable and durable adhesion over 20 cycles. The obtained hydrogels also exhibited good antibacterial activities against Escherichia coli and Staphylococcus aureus because they were based on pyrogallol and borax, which have antibacterial properties. Accordingly, we envision that the PAM-SPI-P/B hydrogels have great potential for use in biomimetic tissues and biosensors.

Bacterial Nanocellulose-Enhanced Alginate Double-Network Hydrogels Cross-Linked with Six Metal Cations for Antibacterial Wound Dressing.

Alginate (Alg) and bacterial nanocellulose (BNC) have exhibited great potential in biomedical applications, especially wound dressing. Non-toxicity and a moisture-maintaining nature are common features making them favorable for functional dressing fabrication. BNC is a natural biopolymer that promotes major advances to the current and future biomedical materials, especially in a flat or tubular membrane form with excellent mechanical strength at hydrated state. The main drawback limiting wide applications of both BNC and Alg is the lack of antibacterial activity, furthermore, the inherent poor mechanical property of Alg leads to the requirement of a secondary dressing in clinical treatment. To fabricate composite dressings with antibacterial activity and better mechanical properties, sodium alginate was efficiently incorporated into the BNC matrix using a time-saving vacuum suction method followed by cross-linking through immersion in separate solutions of six cations (manganese, cobalt, copper, zinc, silver, and cerium). The results showed the fabricated composites had not only pH-responsive antibacterial activities but also improved mechanical properties, which are capable of acting as smart dressings. All composites showed non-toxicity toward fibroblast cells. Rat model evaluation showed the skin wounds covered by the dressings healed faster than by BNC.

Stem Cell Seeded and Silver Nanoparticles Loaded Bilayer PLGA/PVA Dressings for Wound Healing.

Antibacterial activity and promoting wound healing are two important characteristics of ideal dressings. The previous work has successfully prepared a stem cell seeded polyvinyl alcohol (PVA) hydrogel dressing, which could promote wound healing by active factors secreted from the dressing. However, a lack of antibacterial activity might limit its better application. In this study, a photo-active gelatin (Az-Gel) modified stem cell seeded bilayer PVA hydrogel dressings with silver nanoparticles loaded poly(lactic-co-glycolic acid) (PLGA) electrospinning films (Ag-PLGA) in it is prepared. The physical properties of the dressings show the dressings are mechanically enhanced by the addition of Ag-PLGA film. The addition of Ag-PLGA film does not alter the moisture content of PVA, but extends the moisture of the dressing. Obviously, antibacterial activity is observed and Ag-PLGA/PVA scaffold is biocompatible and low toxic to murine dermal fibroblasts (NIH-3T3). When seeded with Adipose-derived stem cells (ADSCs), bioactive factors secreted by ADSCs could penetrate the dressing and promote cell growth and wound healing. It is speculated that the stem cells seeded bilayer dressing would be of great potential for skin tissue engineering, because of its antibacterial activity and safe application of stem cells.

Phenyltriazole-functionalized sulfamate inhibitors targeting tyrosyl- or isoleucyl-tRNA synthetase

Antimicrobial resistance is considered as one of the major threats for the near future as the lack of effective treatments for various infections would cause more deaths than cancer by 2050. The development of new antibacterial drugs is considered as one of the cornerstones to tackle this problem. Aminoacyl-tRNA synthetases (aaRSs) are regarded as good targets to establish new therapies. Apart from being essential for cell viability, they are clinically validated. Indeed, mupirocin, an isoleucyl-tRNA synthetase (IleRS) inhibitor, is already commercially available as a topical treatment for MRSA infections. Unfortunately, resistance developed soon after its introduction on the market, hampering its clinical use. Therefore, there is an urgent need for new cellular targets or improved therapies. Follow-up research by Cubist Pharmaceuticals led to a series of selective and in vivo active aminoacyl-sulfamoyl aryltetrazole inhibitors targeting IleRS (e.g. CB 168).Here, we describe the synthesis of new IleRS and TyrRS inhibitors based on the Cubist Pharmaceuticals compounds, whereby the central ribose was substituted for a tetrahydropyran ring. Various linkers were evaluated connecting the six-membered ring with the base-mimicking part of the synthesized analogues. Out of eight novel molecules, a three-atom spacer to the phenyltriazole moiety, which was established using azide-alkyne click chemistry, appeared to be the optimized linker to inhibit IleRS. However, 11 (Ki,app = 88 ± 5.3 nM) and 36a (Ki,app = 114 ± 13.5 nM) did not reach the same level of inhibitory activity as for the known high-affinity natural adenylate-intermediate analogue isoleucyl-sulfamoyl adenosine (IleSA, CB 138; Ki,app = 1.9 ± 4.0 nM) and CB 168, which exhibit a comparable inhibitory activity as the native ligand. Therefore, 11 was docked into the active site of IleRS using a known crystal structure of T. thermophilus in complex with mupirocin. Here, we observed the loss of the crucial 3′- and 4′- hydroxyl group interactions with the target enzyme compared to CB 168 and mupirocin, which we suggest to be the reason for the limited decrease in enzyme affinity. Despite the lack of antibacterial activity, we believe that structurally optimizing these novel analogues via a structure-based approach could ultimately result in aaRS inhibitors which would help to tackle the antibiotic resistance problem.