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Updated: May 10, 2026
Establishment and Characterization of UTI and CAUTI in a Mouse Model
Published on: June 23, 2015
Bacterial Carbonic Anhydrase Inhibitor CAI0019 Demonstrates Efficacy in Enterococcus faecium Septicemic Peritonitis
Nader S Abutaleb1,2, Katrina J Holly3, Carolyn K Metcalfe3
1Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
Abstract:
Vancomycin-resistant enterococci are multidrug-resistant bacteria that as of 2021 continue to pervade the U.S. healthcare system as the second-most prevalent source of healthcare-acquired infections behind Escherichia coli. Given the limited treatment options for vancomycin-resistant enterococci and growing concerns about antibiotic-induced gut microbiome dysbiosis, there is an urgent need for narrow-spectrum antibiotics that can selectively target vancomycin-resistant enterococci while preserving the integrity of the gut microbiome. Previous studies have demonstrated the in vivo potential of orally dosed acetazolamide-based compounds to reduce vancomycin-resistant enterococci bioburden in the gastrointestinal tract and internal organs of mice. However, while it is hypothesized that these molecules inhibit bacterial carbonic anhydrases, the exact target of the acetazolamide scaffold in vancomycin-resistant enterococci has remained unconfirmed. Additionally, the impact of the scaffold on in vivo gut microbiome diversity remains uncharacterized. The work herein reports the chemoproteomic identification of α-carbonic anhydrase as the primary target of the acetazolamide scaffold in E. faecium and presents its uniqueness as a narrow-spectrum antibiotic target that can be exploited by CAI0019, a lead acetazolamide derivative with in vivo efficacy, while sparing gut microbiome diversity in mice. This work presents compelling data that not only confirm α-carbonic anhydrase as an antibiotic target in Enterococcus but also demonstrate that narrow-spectrum in vivo antienterococcal efficacy can be achieved through targeting α-carbonic anhydrase such that gut commensal microbiota remain unimpacted.
Insights
Vancomycin-resistant enterococci (VRE) are a growing threat. Researchers identified alpha-carbonic anhydrase as the VRE target for a new narrow-spectrum antibiotic, CAI0019, which effectively reduces VRE without harming the gut microbiome.
Area of Science:
- Microbiology
- Drug Discovery
- Medical Chemistry
Background:
- Vancomycin-resistant enterococci (VRE) are a significant cause of healthcare-associated infections.
- Limited treatment options and concerns about microbiome disruption necessitate novel narrow-spectrum antibiotics.
- Previous studies suggested acetazolamide-based compounds could reduce VRE, but the target was unconfirmed.
Purpose of the Study:
- To identify the specific molecular target of acetazolamide derivatives in VRE.
- To evaluate the efficacy and microbiome impact of a lead compound, CAI0019.
- To confirm alpha-carbonic anhydrase as a viable narrow-spectrum antibiotic target.
Main Methods:
- Chemoproteomic analysis to identify the drug target in Enterococcus faecium.
- In vivo studies in mice to assess VRE bioburden reduction.
- Analysis of gut microbiome diversity following treatment with CAI0019.
Main Results:
- Alpha-carbonic anhydrase was identified as the primary target of the acetazolamide scaffold in E. faecium.
- CAI0019 demonstrated in vivo efficacy in reducing VRE.
- Treatment with CAI0019 preserved gut microbiome diversity in mice.
Conclusions:
- Alpha-carbonic anhydrase is a validated narrow-spectrum antibiotic target for VRE.
- CAI0019 effectively targets VRE while sparing the gut microbiome.
- This approach offers a promising strategy for combating VRE infections.
