2. Academic Validation
  3. Development of Penicillin-Based Carbonic Anhydrase Inhibitors Targeting Multidrug-Resistant Neisseria gonorrhoeae

Development of Penicillin-Based Carbonic Anhydrase Inhibitors Targeting Multidrug-Resistant Neisseria gonorrhoeae

  • J Med Chem. 2024 Jun 13;67(11):9613-9627. doi: 10.1021/acs.jmedchem.4c00740.
Alessandro Bonardi 1,  Alessio Nocentini 1,  Simone Giovannuzzi 1,  Niccolò Paoletti 1,  Andrea Ammara 1,  Silvia Bua 2,  Nader S Abutaleb 3,  Abdallah S Abdelsattar 3,  Clemente Capasso 4,  Paola Gratteri 1,  Daniel P Flaherty 5,  Mohamed N Seleem 3 6,  Claudiu T Supuran 1
Affiliations

Affiliations

  • 1 NEUROFARBA Department, Pharmaceutical and Nutraceutical Section and Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Via U. Schiff 6, Sesto Fiorentino, Florence 50019, Italy.
  • 2 Research Institute of the University of Bucharest (ICUB), Bucharest 050663, Romania.
  • 3 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
  • 4 Istituto di Bioscienze e Biorisorse, CNR, Naples 80131, Italy.
  • 5 Borch Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
  • 6 Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, United States.
PMID: 38776401 DOI: 10.1021/acs.jmedchem.4c00740
Abstract

The development of Antibacterial drugs with new mechanisms of action is crucial in combating the rise of antibiotic-resistant infections. Bacterial carbonic anhydrases (CAs, EC 4.2.1.1) have been validated as promising Antibacterial targets against pathogens such as Helicobacter pylori, Neisseria gonorrhoeae, and vancomycin-resistant enterococci. A multitarget strategy is proposed to design penicillin-based CA Inhibitor hybrids for tackling resistance by targeting multiple Bacterial pathways, thereby resensitizing drug-resistant strains to clinical Antibiotics. The sulfonamide derivatives potently inhibited the CAs from N. gonorrhoeae and Escherichia coli with KI values in the range of 7.1-617.2 nM. Computational simulations with the main penicillin-binding protein (PBP) of N. gonorrhoeae indicated that these hybrid derivatives maintained the mechanism of action of the lead β-lactams. A subset of derivatives showed potent PBP-related antigonococcal effects against multidrug-resistant N. gonorrhoeae strains, with several compounds significantly outperforming both the lead β-lactam and CA Inhibitor drugs (MIC values in the range 0.25 to 0.5 μg/mL).

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