Targeting amino acid biosynthesis pathways for antibacterial drug discovery: Chemical lessons and design opportunities.

Abstract

Antimicrobial resistance (AMR) remains a major health challenge, emphasizing the urgent need for novel antibacterial strategies and unexplored therapeutic targets. Amino acid biosynthesis pathways are largely absent in humans but are central to bacterial growth, virulence, and metabolic adaptation, making them an attractive yet underexploited target space for antibacterial drug discovery. This review examines bacterial amino acid metabolism through a medicinal chemistry lens, focusing on prioritized and emerging enzyme targets with meaningful inhibitor development, structure-activity relationship (SAR), cellular activity, or target validation. Although several amino acid inhibitors have achieved commercial success as herbicides, their limited translation into antibacterial therapeutics is examined through representative case studies that highlight enzyme structural divergence, permeability barriers, target-engagement gaps, resistance risks, and the need for bacterial-specific optimization. We discuss recurring bottlenecks, promising recent advances, and practical design lessons while emphasizing the enzymatic, structural, functional, and regulatory features that define target tractability.