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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月14日

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  • Reuben S. Maghembe

摘要

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.