Challenges for developing bacterial CA inhibitors as novel antibiotics

Area of Science:

• Biochemistry
• Microbiology
• Drug Discovery

Background:

• Classical sulfonamide carbonic anhydrase inhibitors (CAIs) primarily target human enzymes.
• Bacterial carbonic anhydrases (CAs) from various pathogens are viable drug targets.
• Existing CAIs demonstrate efficacy against bacterial CAs, including those from resistant strains.

Purpose of the Study:

• To explore the repurposing of human carbonic anhydrase inhibitors (CAIs) as antibacterial agents.
• To discuss strategies for developing CAIs with enhanced selectivity for bacterial versus human enzymes.
• To address the challenge of antimicrobial resistance, particularly to beta-lactams.

Main Methods:

• Inhibition assays of bacterial carbonic anhydrases (CAs) using classical CAIs.
• Evaluation of CAI effects on bacterial growth, virulence, and antibiotic resensitization.
• Discussion of strategies for selective CAI development.

Main Results:

• Classical CAIs effectively inhibit bacterial CAs across different classes (α, β, γ).
• Treatment with CAIs impaired bacterial growth and reduced virulence in pathogens like *Helicobacter pylori* and *Mycobacterium tuberculosis*.
• CAIs resensitized drug-resistant bacteria to existing antibiotics.

Conclusions:

• Classical CAIs are promising candidates for antibacterial drug repurposing.
• Developing selective CAIs targeting bacterial CAs is crucial for combating antimicrobial resistance.
• Selective CAIs could be a vital tool against beta-lactam-resistant bacteria and other pathogens.