Utilizing nanomaterials as an alternative to antibiotics, with a focus on maintaining high biosafety, has emerged as a promising strategy to combat antibiotic resistance. Nevertheless, the challenge lies in the indiscriminate attack of nanomaterials on both bacterial and mammalian cells, which limits their practicality. Herein, Cu3SbS3 nanoparticles (NPs) capable of generating reactive oxygen species (ROS) are discovered to selectively adsorb and eliminate bacteria without causing obvious harm to mammalian cells, thanks to the interaction between O of N-acetylmuramic acid in bacterial cell walls and Cu of the NPs. Coupled with the short diffusion distance of ROS in the surrounding medium, a selective antibacterial effect is achieved. Additionally, the antibacterial mechanism is then identified: Cu3SbS3 NPs catalyze the generation of O2•-, which has subsequently been conversed by superoxide dismutase to H2O2. The latter is secondary catalyzed by the NPs to form •OH and 1O2, initiating an in situ attack on bacteria. This process depletes bacterial glutathione in conjunction with the disruption of the antioxidant defense system of bacteria. Notably, Cu3SbS3 NPs are demonstrated to efficiently impede biofilm formation; thus, a healing of MRSA-infected wounds was promoted. The bacterial cell wall-binding nanoantibacterial agents can be widely expanded through diversified design.

BACKGROUND: Staphylococcus aureus, a commensal bacterium, colonizes the skin and mucous membranes of approximately 30% of the human population. Apart from conventional resistance mechanisms, one of the pathogenic features of S. aureus is its ability to survive in a biofilm state on both biotic and abiotic surfaces. Due to this characteristic, S. aureus is a major cause of human infections, with Methicillin-Resistant Staphylococcus aureus (MRSA) being a significant contributor to both community-acquired and hospital-acquired infections.
RESULTS: Analyzing non-repetitive clinical isolates of MRSA collected from seven provinces and cities in China between 2014 and 2020, it was observed that 53.2% of the MRSA isolates exhibited varying degrees of ability to produce biofilm. The biofilm positivity rate was notably high in MRSA isolates from Guangdong, Jiangxi, and Hubei. The predominant MRSA strains collected in this study were of sequence types ST59, ST5, and ST239, with the biofilm-producing capability mainly distributed among moderate and weak biofilm producers within these ST types. Notably, certain sequence types, such as ST88, exhibited a high prevalence of strong biofilm-producing strains. The study found that SCCmec IV was the predominant type among biofilm-positive MRSA, followed by SCCmec II. Comparing strains with weak and strong biofilm production capabilities, the positive rates of the sdrD and sdrE were higher in strong biofilm producers. The genetic determinants ebp, icaA, icaB, icaC, icaD, icaR, and sdrE were associated with strong biofilm production in MRSA. Additionally, biofilm-negative MRSA isolates showed higher sensitivity rates to cefalotin (94.8%), daptomycin (94.5%), mupirocin (86.5%), teicoplanin (94.5%), fusidic acid (81.0%), and dalbavancin (94.5%) compared to biofilm-positive MRSA isolates. The biofilm positivity rate was consistently above 50% in all collected specimen types.
CONCLUSIONS: MRSA strains with biofilm production capability warrant increased vigilance.

Inspired by glycyrrhizin\'s strong pharmacological activities and the directed self-assembly into hydrogels, we created a novel carrier-free, injectable hydrogel (CAR@glycygel) by combining glycyrrhizin with carvacrol (CAR), without any other chemical crosslinkers, to promote wound healing on bacteria-infected skin. CAR appeared to readily dissolve and load into CAR@glycygel. CAR@glycygel had a dense, porous, sponge structure and strong antioxidant characteristics. In vitro, it showed better antibacterial ability than free CAR. For methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Escherichia coli, the diameter of inhibition zone values of CAR@glycygel were 3.80 ± 0.04, 3.31 ± 0.20 and 3.12 ± 0.24 times greater, respectively, than those of free CAR. The MICs for CAR@glycygel was 156.25 μg/mL while it was 1250.00 μg/mL for free CAR to these three bacteria. Its antibacterial mechanism appeared to involve destruction of the integrity of the bacterial cell wall and biomembrane, leading to a leakage of AKP and inhibition of biofilm formation. In vivo, CAR@glycygel effectively stopped bleeding. When applied to skin wounds on rats infected with MRSA, CAR@glycygel had strong bactericidal activity and improved wound healing. The wound healing rates for CAR@glycygel were 49.59 ± 15.78 %, 93.02 ± 3.09 % and 99.02 ± 0.55 % on day 3, day 7, and day 11, respectively, which were much better than blank control and positive control groups. Mechanisms of CAR@glycygel accelerating wound healing involved facilitating epidermis remolding, promoting the growth of hair follicles, stimulating collagen deposition, mitigating inflammation, and promoting angiogenesis. Overall, CAR@glycygel showed great potential as wound dressing for infected skin wounds.

Methicillin-resistant Staphylococcus aureus (MRSA), a notorious bacterium with high drug resistance and easy recurrence after surgery, has posed significant clinical treatment challenges. In the current scarcity of new antibiotics, the identification of adjuvants to existing antibiotics is a promising approach to combat infections caused by multidrug-resistant Gram-positive bacteria. The in vitro synergy test, which included a MIC assay, time-kill curve, antimicrobial susceptibility testing, and live/dead bacteria staining assay, revealed that laurocapram, a widely used chemical transdermal enhancer, could potentiate the antibacterial activity of cephalosporins against MRSA. In vitro, laurocapram combined with cefixime showed an excellent synergistic activity against MRSA (FICI = 0.28 ± 0.00). In addition, the combination of laurocapram and cefixime may inhibited the formation of MRSA biofilm and caused cell membrane damage. Following that, we discovered that combining laurocapram with cefixime could alleviate the symptoms of mice in the MRSA skin infection model and the MRSA pneumonia model. In conclusion, laurocapram is a promising and low-cost antibacterial adjuvant, providing a new strategy for further exploring the use of lower doses of cephalosporins to combat MRSA infection.

Nanomaterial-based synergistic antibacterial agents are considered as promising tools to combat infections caused by antibiotic-resistant bacteria. Herein, multifunctional mesoporous silica nanoparticle (MSN)-based nanocomposites were fabricated for synergistic photothermal/photodynamic/chemodynamic therapy against methicillin-resistant Staphylococcus aureus (MRSA). MSN loaded with indocyanine green (ICG) as a core, while Prussian blue (PB) nanostructure was decorated on MSN surface via in situ growth method to form a core-shell nanohybrid (MSN-ICG@PB). Upon a near infrared (NIR) laser excitation, MSN-ICG@PB (200 μg mL-1) exhibited highly efficient singlet oxygen (1O2) generation and hyperthermia effect (48.7℃). In the presence of exogenous H2O2, PB with peroxidase-like activity promoted the generation of toxic hydroxyl radicals (•OH) to achieve chemodynamic therapy (CDT). PTT can greatly increase the permeability of bacterial lipid membrane, facilitating the generated 1O2 and •OH to kill bacteria more efficiently. Under NIR irradiation and exogenous H2O2, MSN-ICG@PB (200 μg mL-1) with good biocompatibility exhibited a synergistic antibacterial effect against MRSA with high bacterial killing efficiency (>98 %). Moreover, due to the synergistic bactericidal mechanism, MSN-ICG@PB with satisfactory biosafety makes it a promising antimicrobial agent to fight against MRSA.

Multi-drug-resistant Staphylococcus aureus infections necessitate novel antibiotic development. D-3263, a transient receptor potential melastatin member 8 (TRPM8) agonist, has potential antineoplastic properties. Here, we reported the antibacterial and antibiofilm activities of D-3263. Minimum inhibitory concentrations (MICs) against S. aureus, Enterococcus faecalis and E. faecium were ≤ 50 µM. D-3263 exhibited bactericidal effects against clinical methicillin-resistant S. aureus (MRSA) and E. faecalis strains at 4× MIC. Subinhibitory D-3263 concentrations effectively inhibited S. aureus and E. faecalis biofilms, with higher concentrations also clearing mature biofilms. Proteomic analysis revealed differential expression of 29 proteins under 1/2 × MIC D-3263, influencing amino acid biosynthesis and carbohydrate metabolism. Additionally, D-3263 enhanced membrane permeability of S. aureus and E. faecalis. Bacterial membrane phospholipids phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) dose-dependently increased D-3263 MICs. Overall, our data suggested that D-3263 exhibited potent antibacterial and antibiofilm activities against S. aureus by targeting the cell membrane.

UNASSIGNED: This research was to innovate a nanozyme-based therapeutic strategy that combines aggregation-induced emission (AIE) photosensitizers with copper nanozymes. This approach is designed to address the hypoxic conditions often found in bacterial infections and aims to boost the effectiveness of photodynamic therapy (PDT) by ensuring sufficient oxygen supply for reactive oxygen species (ROS) generation.
UNASSIGNED: Our approach involved the synthesis of dihydroxyl triphenyl vinyl pyridine (DHTPY)-Cu@zoledronic acid (ZOL) nanozyme particles. We initially synthesized DHTPY and then combined it with copper nanozymes to form the DHTPY-Cu@ZOL composite. The nanozyme\'s size, morphology, and chemical properties were characterized using various techniques, including dynamic light scattering, transmission electron microscopy, and X-ray photoelectron spectroscopy. We conducted a series of in vitro and in vivo tests to evaluate the photodynamic, antibacterial, and wound-healing properties of the DHTPY-Cu@ZOL nanozymes, including their oxygen-generation capacity, ROS production, and antibacterial efficacy against methicillin-resistant Staphylococcus aureus (MRSA).
UNASSIGNED: The DHTPY-Cu@ZOL exhibited proficient H2O2 scavenging and oxygen generation, crucial for enhancing PDT in oxygen-deprived infection environments. Our in vitro analysis revealed a notable antibacterial effect against MRSA, suggesting the nanozymes\' potential to disrupt bacterial cell membranes. Further, in vivo studies using a diabetic rat model with MRSA-infected wounds showed that DHTPY-Cu@ZOL markedly improved wound healing and reduced bacterial presence, underscoring its efficacy as a non-antibiotic approach for chronic infections.
UNASSIGNED: Our study suggests that DHTPY-Cu@ZOL is a highly promising approach for combating antibiotic-resistant microbial pathogens and biofilms. The biocompatibility and stability of these nanozyme particles, coupled with their improved PDT efficacy position them as a promising candidate for clinical applications.

The overuse of antibiotics in animal farming and aquaculture has led to multidrug-resistant methicillin-sensitive Staphylococcus aureus (MR-MSSA) becoming a common pathogen in foodborne diseases. Sophora flavescens Ait. serves as a traditional plant antibacterial agent and functional food ingredient. A total of 30 compounds (1-30) were isolated from the root bark of S. flavescens, consisting of 20 new compounds (1-20). In the biological activity assay, compound 1 demonstrated a remarkable inhibitory effect on MR-MSSA, with an MIC of 2 μg/mL. Furthermore, 1 was found to rapidly eliminate bacteria, inhibit biofilm growth, and exhibit exceptionally low cytotoxicity. Mechanistic studies have revealed that 1 possesses an enhanced membrane-targeting ability, binding to the bacterial cell membrane components phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and cardiolipin (CL). This disruption of bacterial cell membrane integrity increases intracellular reactive oxygen species, protein and DNA leakage, reduced bacterial metabolism, and ultimately bacterial death. In summary, these findings suggest that compound 1 holds promise as a lead compound against MR-MSSA.

Isoflavones are a class of natural products that exhibit a wide range of interesting biological properties, including antioxidant, hepatoprotective, antimicrobial, and anti-inflammatory activities. Scandenone (1), osajin (2), and 6,8-diprenylgenistein (3) are natural prenylated isoflavones that share the same polyphenol framework. In this research, the key intermediate 15 was used for the synthesis of the natural isoflavones 1-3, establishing a stereoselective synthetic method for both linear and angular pyran isoflavones. The antibacterial activities of 1-3 were also evaluated, and all of them displayed good antibacterial activity against Gram-positive bacteria. Among them, 2 was the most potent one against MRSA, with a MIC value of 2 μg/mL, and the SEM assay indicated that the bacterial cell membranes of both MRSA and E. faecalis could be disrupted by 2. These findings suggest that this type of isoflavone could serve as a lead for the development of novel antibacterial agents for the treatment of Gram-positive bacterial infections.

Propolis has potential anti-inflammatory properties, but little is known about its efficacy against inflammatory reactions caused by drug-resistant bacteria, and the difference in efficacy between propolis and tree gum is also unclear. Here, an in vivo study was performed to study the effects of ethanol extract from poplar propolis (EEP) and poplar tree gum (EEG) against heat-inactivated methicillin-resistant Staphylococcus aureus (MRSA)-induced acute lung injury (ALI) in mice. Pre-treatment with EEP and EEG (100 mg/kg, p.o.) resulted in significant protective effects on ALI in mice, and EEP exerted stronger activity to alleviate lung tissue lesions and ALI scores compared with that of EEG. Furthermore, EEP significantly suppressed the levels of pro-inflammatory mediators in the lung, including TNF-α, IL-1β, IL-6, and IFN-γ. Gut microbiota analysis revealed that both EEP and EEG could modulate the composition of the gut microbiota, enhance the abundance of beneficial microbiota and reduce the harmful ones, and partly restore the levels of short-chain fatty acids. EEP could modulate more serum metabolites and showed a more robust correlation between serum metabolites and gut microbiota. Overall, these results support the anti-inflammatory effects of propolis in the treatment of ALI, and the necessity of the quality control of propolis.