Designing the Next Generation of Antibiotics: Structure, SAR, and Strategy in Medicinal Chemistry (2000-2025).

Antibacterial agents remain vital for managing infectious diseases, yet the global escalation of antimicrobial resistance (AMR) continues to compromise their therapeutic effectiveness. Despite decades of discovery and chemical refinement, most recently developed antibacterials belong to existing structural classes, underscoring a pressing need for innovative molecular scaffolds and mechanisms of action. This review provides a comprehensive medicinal-chemistry overview of major antibacterial classes, including β-lactams, glycopeptides, tetracyclines, fluoroquinolones, macrolides, aminoglycosides, oxazolidinones, polymyxins, and lipopeptides. The discussion emphasizes their structural frameworks, key structure-activity relationship (SAR) features, and the chemical strategies used to enhance potency, spectrum, and pharmacokinetic properties while counteracting bacterial resistance mechanisms. In addition, emerging developments in the antibacterial pipeline-covering new, withdrawn, discontinued, and clinically advancing compounds (2000-2025)-are highlighted to reflect the current state of innovation in antibiotic discovery. By integrating chemical, pharmacological, and developmental insights, this review aims to provide a clear and updated perspective on how medicinal chemistry continues to shape the design and evolution of antibacterial therapeutics in the face of rising resistance.