Methicillin-resistant Staphylococcus aureus (MRSA) is considered to be a worldwide threat to human health and the global spread of MRSA has been associated with the emergence of different types of infections and resultant selection pressure due to exposure to many antibiotics. In the current era characterized by incessant antibiotic resistance, assessment of multiple molecular targets represents notable therapeutic opportunities in the medical and pharmaceutical industry and can aid in the discovery of novel molecules that inhibit various receptors effectively to replace the current weak antimicrobial agents. Penicillin binding protein 2a (PBP2a) of MRSA is a major determinant of resistance to β-lactam antibiotics. The activity of PBP2a is not inhibited by β-lactam antibiotics, allowing the strain to survive in the presence of β-lactams leading to resistance to β-lactam antibiotics. The study aimed at identifying potential inhibitors of PBP2a receptor of MRSA through ligand-based pharmacophore modeling, 2D-QSAR, structure-based drug design docking and molecular dynamic (MD) simulations. The study led to the development of a satisfactory, predictive and significant 2D-QSAR model for predicting anti-MRSA activity of compounds and also led to the identification of two molecules: C ₂₁ H ₂₅ N ₇ O ₄ S ₂ (ChEMBL30602) and C ₂₀ H ₁₇ NO ₆ S (ChEMBL304837) with favorable pharmacophore features and ADME properties with potential to bind strongly to PBP2a receptor of MRSA. MD simulation analysis showed that the interactions of C ₂₀ H ₁₇ NO ₆ S (ChEMBL304837) with PBP2a over 100 ns was more stable and similar to the interaction of ceftobiprole with PBP2a and may become potential drug candidate against MRSA which has developed a lot of resistance to current antibiotics.

World Health Organization recommend the use of malaria vaccine, Mosquirix, as a malaria prevention strategy. However, Mosquirix has failed to reduce the global burden of malaria because of its inefficacy. The Mosquirix vaccine’s modest effectiveness against malaria, 36% among kids aged 5 to 17 months who need at least four doses, fails to aid malaria eradication. Therefore, highly effective and efficacious malaria vaccines are required. The well-characterized P. falciparum circumsporozoite surface protein can be used to discover adjuvants that can increase the efficacy of Mosquirix. Therefore, the study sought to undertake an in-silico discovery of Plasmodium falciparum circumsporozoite surface protein inhibitors with pharmacological properties on Mosquirix using hierarchical virtual screening and molecular dynamics simulation. Monoclonal antibody L9, an anti-Plasmodium falciparum circumsporozoite surface protein molecule, was used to identify Plasmodium falciparum circumsporozoite surface protein inhibitors with pharmacological properties on Mosquirix during a virtual screening process in ZINCPHARMER that yielded 23 hits. After drug-likeness and absorption, distribution, metabolism, excretion, and toxicity property analysis in the SwissADME web server, only 9 of the 23 hits satisfied the requirements. The 9 compounds were docked with Plasmodium falciparum circumsporozoite surface protein using the PyRx software to understand their interactions. ZINC25374360 (−8.1 kcal/mol), ZINC40144754 (−8.3 kcal/mol), and ZINC71996727 (−8.9 kcal/mol) bound strongly to Plasmodium falciparum circumsporozoite surface protein with binding affinities of less than −8.0 kcal/mol. The stability of these molecularly docked Plasmodium falciparum circumsporozoite surface protein-inhibitor complexes were assessed through molecular dynamics simulation using GROMACS 2022. ZINC25374360 and ZINC71996727 formed stable complexes with Plasmodium falciparum circumsporozoite surface protein. They were subjected to in vitro validation for their inhibitory potential. The IC50 values ranging between 250 and 350 ng/ml suggest inhibition of parasite development. Therefore, the two Plasmodium falciparum circumsporozoite surface protein inhibitors can be used as vaccine adjuvants to increase the efficacy of the existing Mosquirix vaccine. Nevertheless, additional in vivo tests, structural optimization studies, and homogenization analysis are essential to determine the anti-plasmodial action of these adjuvants in humans.

Antimicrobial resistance is a critical global health threat, as conventional antibiotics are increasingly ineffective against multidrug-resistant (MDR) pathogens, particularly ESKAPE organisms. In response, bacteriophages and their derived lytic proteins, including endolysins, holins, and spanins, have emerged as promising therapeutic alternatives. This review examines the current landscape and future prospects of phage-based therapeutics within a One Health framework spanning human, veterinary, and environmental applications. We explore phage biology, including both lytic and lysogenic cycles, as a mechanistic foundation for understanding their role in addressing the growing threat of antimicrobial resistance. Additionally, we detail bacterial defence mechanisms, such as restriction modification systems, CRISPR-Cas systems, and spontaneous mutations that confer phage resistance. Lytic proteins demonstrate efficacy in treating systemic infections, disrupting biofilm, and targeting resistant pathogens across humans, livestock, and aquaculture. Although phage therapy is a promising antibacterial alternative, it still faces several constraints, including a narrow host range, immune clearance, complex pharmacokinetics, and the inability of exogenous lytic proteins to cross the outer membranes of Gram-negative bacteria. This review highlights emerging solutions to these challenges, including the use of artificial intelligence (AI) for phage and lysin discovery, machine learning models for predicting effective phage combinations, and the engineering of phage lytic proteins to broaden antimicrobial spectra. It also discusses combination strategies that pair whole phages with their derived proteins to exploit synergistic killing and counter the emergence of resistance, as well as advanced delivery systems designed to protect phage integrity and enhance activity in hostile physiological environments.

Antimicrobial resistance is a critical global health threat, as conventional antibiotics are increasingly ineffective against multidrug-resistant (MDR) pathogens, particularly ESKAPE organisms. In response, bacteriophages and their derived lytic proteins, including endolysins, holins, and spanins, have emerged as promising therapeutic alternatives. This review examines the comparative therapeutic potential of phages and phage-derived lytic proteins as complementary antibacterial strategies within a One-Health framework, which remains underdeveloped. We explore phage biology, including both lytic and lysogenic cycles, as a mechanistic foundation for understanding their role in addressing the growing threat of antimicrobial resistance. Additionally, we detail bacterial defense mechanisms, such as restriction modification systems, CRISPR-Cas systems, and spontaneous mutations that confer phage resistance. Lytic proteins demonstrate efficacy in treating systemic infections, disrupting biofilm, and targeting resistant pathogens across humans, livestock, and aquaculture. Although phage therapy is a promising antibacterial alternative, it still faces several constraints, including a narrow host range, immune clearance, complex pharmacokinetics, and the inability of exogenous lytic proteins to cross the outer membranes of Gram-negative bacteria. This review highlights emerging solutions to these challenges, including the use of artificial intelligence (AI) for phage and lysin discovery, machine learning models for predicting effective phage combinations, and the engineering of phage lytic proteins to broaden antimicrobial spectra. It also discusses combination strategies that pair whole phages with their derived proteins to exploit synergistic antibacterial effects and counter the emergence of resistance, as well as advanced delivery systems designed to protect phage integrity and enhance activity in hostile physiological environments.

The World Health Organization (WHO) documents malaria as one of the leading causes of high morbidity and mortality worldwide. The disease affects millions and kills thousands of people annually. Efforts to reduce the global burden of malaria have prompted WHO to recommend prevention strategies like using anti-malarial drugs. However, these strategies have been ineffective because of anti-malarial drug resistance. The only efficacious malaria treatment is Artemisinin-based Combination Therapy (ACT). However, the extended ACTs clearance times, linked to the emergence of artemisinin monotherapy resistance recorded most recently in Africa and the Great Mekong region, pose a danger to its efficacy. Therefore, better efficacious malaria drugs are required. Since P. falciparum heat shock protein 90 (PfHsp90) is a well-characterized malaria drugs target, this study uses it to discover more efficacious malaria drugs. An in-silico approach was used to discover PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria using molecular dynamics simulation (MDS) and hierarchical virtual screening. Geldanamycin (GDM), a well-known anti-PfHsp90 compound, was used to identify PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria by screening it against the ZINC database via the ZINCPHARMER web server. This virtual screening process resulted in 17 hits. These ZINCPHARMER hits were subjected to drug-likeness and pharmacokinetics properties analysis in the SwissADME web server, and 9 of them satisfied the requirements. The 9 ZINC compounds were docked with PfHsp90 using the PyRx software to understand their interactions. From the molecular docking results, ZINC09060002 (-8.2 kcal/mol), ZINC72133064 (-7.8 kcal/mol), ZINC72163401 (-7.7 kcal/mol), ZINC72358537 (-8.1 kcal/mol), and ZINC72358557 (-7.6 kcal/mol) had better binding affinities to PfHsp90 than GDM (-7.5 kcal/mol). The stability of these molecularly docked protein-inhibitor complexes was assessed through MDS using GROMACS 2022. ZINC72163401, ZINC72358537, and ZINC72358557 formed stable complexes with PfHsp90. The lead compounds were subjected to in vitro validation for their inhibitory capability. They showed promising inhibition of parasite growth with IC50 values ranging between 200 – 400 ng/ml. In this regard, the three PfHsp90 inhibitors can be used as anti-malarial drugs. However, further structural optimization studies and clinical (in vivo) tests are necessary to ascertain the antimalarial activity of these compounds in humans.