Inhibition of <i>Pseudomonas aeruginosa</i> Carbonic Anhydrases, Exploring Ciprofloxacin Functionalization Toward New Antibacterial Agents: An In-Depth Multidisciplinary Study
Ciprofloxacin (CPX) is one of the most employed antibiotics in clinics to date. However, the rise of drug-resistant bacteria is dramatically impairing its efficacy, especially against life-threatening pathogens, such as <i>Pseudomonas aeruginosa</i>. This Gram-negative bacterium is an opportunistic pathogen, often infecting immuno-compromised patients with severe or fatal outcomes. The evidence of the possibility of exploiting Carbonic Anhydrase (CA, EC: 4.2.1.1) enzymes as pharmacological targets along with their role in <i>P. aeruginosa</i> virulence inspired the derivatization of CPX with peculiar CA-inhibiting chemotypes. Thus, a large library of CPX derivatives was synthesized and tested on a panel of bacterial CAs and human isoenzymes I and II. Selected derivatives were evaluated for antibacterial activity, revealing bactericidal and antibiofilm properties for some compounds. Importantly, promising preliminary absorption, distribution, metabolism, and excretion (ADME) properties <i>in vitro</i> were found and no cytotoxicity was detected for some representative compounds when tested in <i>Galleria mellonella</i> larvae.
Authors
- Susi Zara (ORCID: https://orcid.org/0000-0003-1705-6943)
- Francesco Melfi (ORCID: https://orcid.org/0000-0003-1987-0850)
- Orazio Nicolotti (ORCID: https://orcid.org/0000-0001-6533-5539)
- Marta Ferraroni (ORCID: https://orcid.org/0000-0001-7258-738X)
- Rossella Grande (ORCID: https://orcid.org/0000-0002-8432-6889)
- Claudiu T. Supuran (ORCID: https://orcid.org/0000-0003-4262-0323)
- Marianna A. Patrauchan (ORCID: https://orcid.org/0000-0002-0495-3867)
- Clemente Capasso (ORCID: https://orcid.org/0000-0003-3314-2411)
- Benedetta Pellegrini (ORCID: https://orcid.org/0009-0000-1564-9062)
- Anna Rita Tondo (ORCID: https://orcid.org/0000-0003-0874-9828)
- Beatrice Marinacci (ORCID: https://orcid.org/0009-0005-7069-5914)
- Simone Carradori (ORCID: https://orcid.org/0000-0002-8698-9440)
- Fabrizio Carta (ORCID: https://orcid.org/0000-0002-1141-6146)
- Mariangela Agamennone (ORCID: https://orcid.org/0000-0001-5198-0051)
- Valentina Puca (ORCID: https://orcid.org/0000-0002-6417-876X)
- Chiara Vagaggini (ORCID: https://orcid.org/0000-0002-4208-7760)
- Ilaria D’Agostino (ORCID: https://orcid.org/0000-0002-4870-7326)
- Elena Dreassi (ORCID: https://orcid.org/0000-0001-8987-940X)
- Andrea Angeli (ORCID: https://orcid.org/0000-0002-1470-7192)
- Micol Corsiani
Institutions
- University of Siena (IT)
- University of Pisa (IT)
- Oklahoma State University (US)
- University of Chieti-Pescara (IT)
- Institute of Biosciences and Bioresources (IT)
- University of Florence (IT)
- University of Bari Aldo Moro (IT)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-10-25
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01555
- Citations
- 16
- Primary Topic
- Enzyme function and inhibition
- Type
- article
- Field-Weighted Citation Impact
- 3.74
Funders
- Ministero dell'Università e della Ricerca