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<p>Bacterial β-carbonic anhydrases (β-CAs) are actively studied as potential targets for next-generation antibacterial agents. Despite extensive biochemical and structural characterization, their validation as isoform-specific therapeutic targets remains incomplete. Here, we developed and applied a six-filter validation framework—encompassing genetic essentiality, physiological relevance, biochemical feasibility, structural rationale, cellular target engagement, and therapeutic context—to integrate disparate data into a strategic prioritization map across representative pathogens (<i>Escherichia coli, Mycobacterium tuberculosis, Pseudomonas aeruginosa,</i> and <i>Streptococcus pneumoniae</i>). Application of this framework reveals that none of the analyzed β-CA isoforms currently qualifies as a ready therapeutic candidate (Group A), with most falling into context-dependent (Group C) or high-risk (Group D) categories due to specific validation gaps. By systematically defining these gaps, the framework provides a prioritized, target-driven roadmap for future experimental design and antibacterial drug discovery targeting bacterial β-carbonic anhydrases.</p>

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Bacterial β-carbonic anhydrases: a six-step prioritization framework for antibacterial target validation

  • 期刊论文

  • 发表日期：

    2026年3月10日

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  • Mariia Y. Stoliarskaia

摘要

Bacterial β-carbonic anhydrases (β-CAs) are actively studied as potential targets for next-generation antibacterial agents. Despite extensive biochemical and structural characterization, their validation as isoform-specific therapeutic targets remains incomplete. Here, we developed and applied a six-filter validation framework—encompassing genetic essentiality, physiological relevance, biochemical feasibility, structural rationale, cellular target engagement, and therapeutic context—to integrate disparate data into a strategic prioritization map across representative pathogens (Escherichia coli, Mycobacterium tuberculosis, Pseudomonas aeruginosa, and Streptococcus pneumoniae). Application of this framework reveals that none of the analyzed β-CA isoforms currently qualifies as a ready therapeutic candidate (Group A), with most falling into context-dependent (Group C) or high-risk (Group D) categories due to specific validation gaps. By systematically defining these gaps, the framework provides a prioritized, target-driven roadmap for future experimental design and antibacterial drug discovery targeting bacterial β-carbonic anhydrases.