1. Academic Validation
  2. 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.
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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