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.

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.