Antibiotic resistance is an urgent threat to the health and well-being of the world population. It is estimated that by the year 2050 worldwide deaths due to drug-resistant bacteria will outpace those due to cancer. There is an urgent need to identify novel antimicrobial targets and scaffolds to address this threat. Many drug-resistant pathogens express essential carbonic anhydrases and we hypothesize these enzymes represent viable antimicrobial therapeutic targets. To test this hypothesis our team has designed and synthesized novel carbonic anhydrase inhibitor and assessed their efficacy against two prominent drug-resistant pathogens, vancomycin-resistant enterococcus and Neisseria gonorrhoeae. We have shown that these molecules possess potent antimicrobial properties and that the carbonic anhydrases are the intracellular targets. In vitro activity against recombinant forms of the carbonic anhydrases, as well as human isoforms, as well as ligand-bound crystal structures provide a robust structure-activity relationship that will inform future. Finally, we show that leads developed from this project are effective in in vivo assays to protect from and/or clear infections.

Targeting bacterial carbonic anhydrases for treatment of drug-resistant pathogens

ACS Spring Meeting 2021

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