Computational evaluation of efflux pump homologues and lignans as potent inhibitors against multidrug-resistant Salmonella typhi.

Typhoid fever, caused by Salmonella enterica serovar typhi, presents a substantial global health threat, particularly in regions with limited healthcare infrastructure. The rise of multidrug-resistant strains of S. typhi exacerbates this challenge, severely compromising conventional treatment efficacy due to over activity of efflux pumps. In our study, a comprehensive exploration of two fundamental aspects to combat MDR in S. typhi is carried out; i.e. employing advanced bioinformatics analyses and AlphaFold AI, We successfully identified and characterised a putative homologue, ABC-TPA, reminiscent of the P-glycoprotein (P-gp) known for its role in multidrug resistance in diverse pathogens. This discovery provides a critical foundation for understanding the potential mechanisms driving antibiotic resistance in S. typhi. Furthermore, employing computational methodologies, We meticulously assessed the potential of lignans, specifically Schisandrin A, B, and C, as promising Efflux Pump Inhibitors (EPIs) against the identified P-gp homologue in S. typhi. Noteworthy findings revealed robust binding interactions of Schisandrin A and B with the target protein, indicating substantial inhibitory capabilities. In contrast, Schisandrin C exhibited instability, showing varied effectiveness among the evaluated lignans. Pharmacokinetics and toxicity predictions underscored the favourable attributes of Schisandrin A, including prolonged action duration. Furthermore, high systemic stability and demanished toxicity profile of SA and SB present their therapeutic efficacy against MDR. This comprehensive investigation not only elucidates potential therapeutic strategies against MDR strains of S. typhi but also highlights the relevance of computational approaches in identifying and evaluating promising candidates. These findings lay a robust foundation for future empirical studies to address the formidable challenges antibiotic resistance poses in this clinically significant infectious diseases.

Cyclic guanosine monophosphate improves salt tolerance in Solanum lycopersicum.

The cyclic nucleotide cyclic guanosine monophosphate (cGMP) is a powerful cell signaling molecule involved in biotic and abiotic stress perception and signal transduction. In the model plant Arabidopsis thaliana, salt and osmotic stress rapidly induce increase in cGMP which plays role by modulating the activity of monovalent cation transporters, possibly by direct binding to these proteins and by altering the expression of many abiotic stress responsive genes. In a recent study, a membrane permeable analogue of cGMP (8-bromo-cGMP) was found to have a promotive effect on soluble sugar, flavonoids and lignin content, and membrane integrity in Solanum lycopersicum seedlings under salt stress. However, it remains to be elucidated how salt stress affects the endogenous cGMP level in S. lycopersicum and if Br-cGMP-induced improvement in salt tolerance in S. lycopersicum involves altered cation fluxes. The current study was conducted to answer these questions. A rapid increase (within 30 s) in endogenous cGMP level was determined in S. lycopersicum roots after treatment with 100 mM NaCl. Addition of membrane permeable Br-cGMP in growth medium remarkably ameliorated the inhibitory effects of NaCl on seedlings' growth parameters, chlorophyll content and net photosynthesis rate. In salt stressed plants, Br-cGMP significantly decreased Na+ content by reducing its influx and increasing efflux while it improved plants K+ content by reducing its efflux and enhancing influx. Furthermore, supplementation with Br-cGMP improved plant's proline content and total antioxidant capacity, resulting in markedly decreased electrolyte leakage under salt stress. Br-cGMP increased the expression of Na+/H+ antiporter genes in roots and shoots of S. lycopersicum growing under salt stress, potentially enhancing plant's ability to sequester Na+ into the vacuole. The findings of this study provide insights into the mechanism of cGMP-induced salt stress tolerance in S. lycopersicum.

Dental Composites with Magnesium Doped Zinc Oxide Nanoparticles Prevent Secondary Caries in the Alloxan-Induced Diabetic Model.

Antibacterial restorative materials against caries-causing bacteria are highly preferred among high-risk patients, such as the elderly, and patients with metabolic diseases such as diabetes. This study aimed to enhance the antibacterial potential of resin composite with Magnesium-doped Zinc oxide (Mg-doped ZnO) nanoparticles (NPs) and to look for their effectiveness in the alloxan-induced diabetic model. Hexagonal Mg-doped ZnO NPs (22.3 nm diameter) were synthesized by co-precipitation method and characterized through ultraviolet-visible (UV-Vis), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS) analysis. The Mg-doped ZnO NPs (1, 2.5 and 5% w/w) were then evaluated for antibacterial activity using a closed system in vitro biofilm model. Significant enhancement in the antibacterial properties was observed in composites with 1% Mg-doped ZnO compared to composites with bare ZnO reinforced NPs (Streptococcus mutans, p = 0.0005; Enterococcus faecalis, p = 0.0074, Saliva microcosm, p < 0.0001; Diabetic Saliva microcosm, p < 0.0001). At 1−2.5% Mg-doped ZnO NPs concentration, compressive strength and biocompatibility of composites were not affected. The pH buffering effect was also achieved at these concentrations, hence not allowing optimal conditions for the anaerobic bacteria to grow. Furthermore, composites with Mg-doped ZnO prevented secondary caries formation in the secondary caries model of alloxan-induced diabetes. Therefore, Mg-doped ZnO NPs are highly recommended as an antibacterial agent for resin composites to avoid biofilm and subsequent secondary caries formation in high-risk patients.

Effectiveness of Se/ZnO NPs in Enhancing the Antibacterial Activity of Resin-Based Dental Composites.

Biofilm formation in the resin-composite interface is a major challenge for resin-based dental composites. Using doped z nanoparticles (NPs) to enhance the antibacterial properties of resin composites can be an effective approach to prevent this. The present study focused on the effectiveness of Selenium-doped ZnO (Se/ZnO) NPs as an antibacterial nanofiller in resin composites and their impact on their mechanical properties. Pristine and Se/ZnO NPs were synthesized by the mechanochemical method and confirmed through UV-Vis Spectroscopy, FTIR (Fourier Transform Infrared) analysis, X-ray Diffraction (XRD) crystallography, Scanning Electron Microscopy (SEM), Energy Dispersive Spectroscopy (EDS), and Zeta analysis. The resin composites were then modified by varying concentrations of pristine and Se/ZnO NPs. A single species (S. mutans and E. faecalis) and a saliva microcosm model were utilized for antibacterial analysis. Hemolytic assay and compressive strength tests were also performed to test the modified composite resin's cytotoxicity and mechanical strength. When incorporated into composite resin, 1% Se/ZnO NPs showed higher antibacterial activity, biocompatibility, and higher mechanical strength when compared to composites with 1% ZnO NPs. The Se/ZnO NPs has been explored for the first time as an efficient antibacterial nanofiller for resin composites and showed effectiveness at lower concentrations, and hence can be an effective candidate in preventing secondary caries by limiting biofilm formation.

DEAE-Dextran Coated AgNPs: A Highly Blendable Nanofiller Enhances Compressive Strength of Dental Resin Composites.

Micro-crack formation and resultant bacterial infiltration are major causes of secondary caries formation in dental resin-based composite restorations. Improving dental resin composites' mechanical and biological properties using highly bendable nanoparticles (NPs) can resolve this issue. This study aims to develop novel Diethylaminoethyl (DEAE)-Dextran silver nanoparticles (AgNPs) and subsequently modify composite resins with these NPs to enhance their mechanical and antibacterial properties. DEAE-Dextran AgNPs were successfully synthesized using a chemical reduction method that was confirmed with the help of ultraviolet-visible (UV-Vis) spectroscopy, scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), Zeta potential, and energy-dispersive X-ray spectroscopy (EDS). Antibacterial activity of a composite disc with DEAE-Dextran AgNPs was tested against Streptococcus mutans, Enterococcus faecalis, and oral microcosm. The composite discs prepared with DEAE-Dextran AgNPs exhibited excellent antibacterial activity compared with composite resin reinforced by simple AgNPs (p < 0.05). Mechanical properties were significantly enhanced by adding DEAE-Dextran into composite resin (p < 0.05). Moreover, unlike AgNPs, DEAE-Dextran AgNPs were found to be less hemolytic. The results establish strong ground applications for DEAE-Dextran-modified dental composite resins in restorative dental applications.

Ciprofloxacin-Loaded Gold Nanoparticles against Antimicrobial Resistance: An In Vivo Assessment.

Metallic nanoparticles, such as gold nanoparticles (AuNPs), have been extensively studied as drug delivery systems for various therapeutic applications. However, drug-loaded-AuNPs have been rarely explored in vivo for their effect on bacteria residing inside tissues. Ciprofloxacin (CIP) is a second-generation fluoroquinolone with a broad-spectrum of antibiotic properties devoid of developing bacteria resistance. This research is focused on the synthesis and physical characterization of Ciprofloxacin-loaded gold nanoparticles (CIP-AuNPs) and their effect on the colonization of Enterococcus faecalis in the liver and kidneys of mice. The successfully prepared CIP-AuNPs were stable and exerted enhanced in vitro antibacterial activity against E. faecalis compared with free CIP. The optimized CIP-AuNPs were administered (500 µg/Kg) once a day via tail vein to infected mice for eight days and were found to be effective in eradicating E. faecalis from the host tissues. Moreover, unlike CIP, CIP-AuNPs were non-hemolytic. In summary, this study demonstrated that CIP-AuNPs are promising and biocompatible alternative therapeutics for E.-faecalis-induced infections resistant to conventional drugs (e.g., beta-lactams and vancomycin) and should be further investigated.