Targeting upstream and downstream arms of the bacterial shikimate metabolic network as an opportunity for antibacterial and antivirulence therapy

The shikimate pathway is an essential metabolic route in bacteria that generates chorismate, a central intermediate linking primary metabolism to the biosynthesis of aromatic amino acids and diverse infection-relevant metabolites. Its absence in humans and conservation across pathogens make it an attractive target for antimicrobial development. However, despite extensive biochemical characterization, translation of shikimate-pathway inhibition into clinically useful antibiotics has remained limited due to challenges including permeability barriers, metabolic redundancy, and conditional essentiality. Here, I reframe this pathway within a broader shikimate–chorismate metabolic network, integrating canonical enzymatic steps with downstream virulence-associated processes. We synthesize current knowledge on key enzymatic targets, including 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase, 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase, and shikimate kinase, highlighting their structural features, regulatory mechanisms, and known inhibitor classes, including classical compounds such as glyphosate and emerging competitive and allosteric modulators. I further examine chorismate-derived pathways that underpin bacterial fitness and pathogenicity, particularly siderophore biosynthesis systems such as enterobactin, yersiniabactin, and mycobactin, which are critical for iron acquisition in host environments. By integrating enzyme-level inhibition with disruption of virulence-linked metabolic outputs, we propose a dual-targeting strategy that combines growth suppression with attenuation of pathogenic traits. I conclude by discussing key challenges, including pathway plasticity and metabolite salvage, and highlight opportunities for structure-guided and genome-informed antimicrobial discovery. This network-centric framework provides a basis for developing next-generation therapeutics targeting both bacterial metabolism and virulence.