Retention of methicillin susceptibility in Staphylococcus aureus using natural adjuvant as an allosteric modifier of penicillin-binding protein 2a.

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) poses a significant global public health challenge due to its resistance to conventional antibiotics, primarily mediated by the mutated penicillin-binding protein, PBP2a. This study aims to investigate the potential of phytochemicals derived from medicinal plants in the Indian subcontinent to serve as adjuvants, enhancing the efficacy of methicillin against MRSA through allosteric modification of PBP2a using molecular docking and molecular dynamics (MD) simulation. After comprehensive Absorption, Distribution, Metabolism, and Excretion (ADME) profiling, along with AMES and hepatotoxicity tests, 9 compounds were shortlisted as suitable adjuvant candidates. Among them, nimbolide, quercetin, emodin, daidzein, eriodictyol, luteolin, and apigenin exhibited strong binding affinity to the allosteric site of PBP2a, with docking scores ranging from -8.7 to -7.3 kcal/mol. These phytochemicals facilitated enhanced methicillin binding, as evidenced by improved docking scores ranging from -6.1 to -6.8 kcal/mol, compared to -5.6 kcal/mol for methicillin alone. Molecular dynamics simulations confirmed the stability and favorable conformations of phytochemical-PBP2a complexes. Quercetin and daidzein were identified as the most promising adjuvant candidates, forming stable and energetically favorable complexes with PBP2a. Experimental validation showed that quercetin, at 30 mg/mL, effectively retained methicillin's antibacterial efficacy against MRSA. This study underscores the potential of natural compounds in overcoming antibiotic resistance and suggests that phytochemical-antibiotic synergism could be a viable strategy to combat multidrug-resistant bacterial infections.

Mechanistic Approach to Immunity and Immunotherapy of Alzheimer's Disease: A Review.

Alzheimer's disease (AD) is a debilitating neurodegenerative condition characterized by progressive cognitive decline and memory loss, affecting millions of people worldwide. Traditional treatments, such as cholinesterase inhibitors and NMDA receptor antagonists, offer limited symptomatic relief without addressing the underlying disease mechanisms. These limitations have driven the development of more potent and effective therapies. Recent advances in immunotherapy present promising avenues for AD treatment. Immunotherapy strategies, including both active and passive approaches, harness the immune system to target and mitigate AD-related pathology. Active immunotherapy stimulates the patient's immune response to produce antibodies against AD-specific antigens, while passive immunotherapy involves administering preformed antibodies or immune cells that specifically target amyloid-ß (Aß) or tau proteins. Monoclonal antibodies, such as aducanumab and lecanemab, have shown potential in reducing Aß plaques and slowing cognitive decline in clinical trials, despite challenges related to adverse immune responses and the need for precise targeting. This comprehensive review explores the role of the immune system in AD, evaluates the current successes and limitations of immunotherapeutic approaches, and discusses future directions for enhancing the treatment efficacy.

Development of Multi-epitope Based Subunit Vaccine Against Crimean-Congo Hemorrhagic Fever Virus Using Reverse Vaccinology Approach.

Crimean-Congo hemorrhagic fever (CCHF) is a viral disease caused by the Crimean-Congo hemorrhagic fever virus (CCHFV) of the Nairovirus genus. CCHF has occurred endemically in several regions of Africa, Southern Europe, and Central and Southeast Asia, with a case fatality rate of 5 to 80%. The World health organization enlisted CCHF as one of the top prioritized diseases for research and development in emergency contexts that making it a public health concern as no effective vaccine is available till date. Therefore, the present study aims to develop an effective multi-epitope subunit vaccine using immunoinformatics and reverse vaccinology approach against this virus. The B-cell and T-cell epitopes were predicted from structural and non-structural proteins, and filtered by immunogenicity, allergenicity, toxicity, conservancy, and cross-reactivity. The computational analysis revealed that the epitopes could induce an adequate immune response and had strong associations with their respective human leukocyte antigen (HLA) alleles with 98.94% of total world population coverage. Finally, the vaccine with 427 amino acids was constructed by connecting 8 cytotoxic T-lymphocytes, 4 helper T-lymphocytes, and 10 B-cell epitopes with appropriate linkers and ß-defensin as an adjuvant. The antigenicity, allergenicity, solubility, and physiochemical properties of the vaccine were evaluated, followed by structural modelling, refinement, and validation. In addition, molecular docking and molecular dynamic simulations revealed a robust binding affinity and stability of the vaccine-immune receptor complex. Moreover, the codons were optimized for its higher expression in Escherichia coli (E. coli) K12 strain followed by in silico cloning. The proposed subunit vaccine developed in this study could be a potential candidate against CCHFV. However, further experimental validation is required to ensure the immunogenicity and safety profile of the proposed vaccine for combating and eradicating CCHFV. Supplementary Information: The online version contains supplementary material available at 10.1007/s10989-022-10430-0.