2. Academic Validation
  3. Redesigning oxazolidinones as carbonic anhydrase inhibitors against vancomycin-resistant enterococci

Redesigning oxazolidinones as carbonic anhydrase inhibitors against vancomycin-resistant enterococci

  • Eur J Med Chem. 2025 Jul 5:291:117620. doi: 10.1016/j.ejmech.2025.117620.
Andrea Ammara 1,  Simone Giovannuzzi 2,  Alessandro Bonardi 3,  Nader S Abutaleb 4,  Ahmed A Abouelkhair 4,  Daniel P Flaherty 5,  Mohamed N Seleem 4,  Clemente Capasso 6,  Paola Gratteri 3,  Alessio Nocentini 7,  Claudiu T Supuran 8
Affiliations

Affiliations

  • 1 Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Italy; NEUROFARBA Department, Laboratory of Molecular Modeling, Cheminformatics & QSAR, University of Florence, Firenze, Italy.
  • 2 Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Italy. Electronic address: simone.giovannuzzi@unifi.it.
  • 3 NEUROFARBA Department, Laboratory of Molecular Modeling, Cheminformatics & QSAR, University of Florence, Firenze, Italy.
  • 4 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
  • 5 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN, USA; Purdue Institute for Drug Discovery, West Lafayette, IN, USA; Purdue Institute of Inflammation, Immunology and Infectious Disease, West Lafayette, IN, USA.
  • 6 Istituto di Bioscienze e Biorisorse, CNR, 80131, Naples, Italy.
  • 7 Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Italy. Electronic address: alessio.nocentini@unifi.it.
  • 8 Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Italy.
PMID: 40267877 DOI: 10.1016/j.ejmech.2025.117620
Abstract

The rise of vancomycin-resistant enterococci (VRE) as a leading cause of hospital-acquired infections underscores the urgent need for new treatment strategies. In fact, resistance has developed not only to vancomycin but also to Other clinically used agents, such as daptomycin and linezolid. We propose a novel drug design approach merging tedizolid, a second-generation Oxazolidinone used as an unapproved salvage therapy in clinical settings, with Carbonic Anhydrase inhibitors (CAIs) recently validated as functioning decolonization agents. These sulfonamide derivatives showed potent inhibition of the carbonic anhydrases from Enterococcus faecium, with KI values in the range of 14.6-598 nM and 63.2-798 nM against EfCAα and EfCAγ. Computational simulations elucidated the binding mode of these dual-action Antibiotics to the peptidyl transferase center (PTC) of the 50S ribosome subunit and Bacterial CAs. A subset of six derivatives showed potent PTC-related anti-enterococcal effects against multidrug-resistant E. faecalis and E. faecium strains with some compounds outperforming both the Oxazolidinone and CA Inhibitor drugs (MIC values in the range 1-4 μg/mL).

Keywords

Bacterial resistance; Carbonic anhydrase inhibition; Tedizolid; VRE infections; oxazolidinone.

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