In vitro characterization, ADME analysis, and histological and toxicological evaluation of BM1, a macrocyclic amidinourea active against azole-resistant Candida strains
| Autor: | Federica Poggialini, Matteo Borgini, Elena Dreassi, Maurizio Botta, Rajendra Prasad, Ilaria D'Agostino, Giuseppina I. Truglio, Cecilia Martini, Nitesh Kumar Khandelwal, Diego Fiorucci, Laura Maccari, Claudio Zamperini, Francesca Bugli, Jacques F. Meis, Riccardo Torelli, Francesco Orofino, Micaela Bernabei, Maurizio Sanguinetti |
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| Rok vydání: | 2020 |
| Předmět: |
Microbiology (medical)
Azoles Antifungal Agents Drug Resistance ATP-binding cassette transporter Microbial Sensitivity Tests Biology Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA Microbiology All institutes and research themes of the Radboud University Medical Center Pharmacokinetics In vivo Drug Resistance Fungal ADME antifungal Candida in vitro in vivo pharmacokinetics Animals Candidiasis Guanidine Rats Urea Distribution (pharmacology) Pharmacology (medical) chemistry.chemical_classification In vitro toxicology ADMET Antifungal In vitro General Medicine Infectious Diseases Fungal lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] chemistry Azole |
| Zdroj: | International Journal of Antimicrobial Agents, 55, 3 International Journal of Antimicrobial Agents, 55 |
| ISSN: | 0924-8579 |
| Popis: | Background : Among the opportunistic fungi, Candida species represent one of the most common causes of nosocomial bloodstream infections. The large use of antifungal agents, most of them launched on the market more than twenty years ago, led to the selection of drug-resistant or even multidrug-resistant fungi. In the last years, we described a novel class of antifungal macrocyclic compounds bearing an amidinourea moiety, highly active against various azole-resistant Candida strains. Objective : In this study, one representative of this family, compound BM1, has been investigated on its in vitro activity against various Candida species, including C. auris isolates, its interaction with the ABC transporter CDR6 and its in vivo distribution and safety. Methods : In vitro assays (CYP inhibition, microsomal stability, permeability, spot assays) have been used to collect chemical and biological data; animal models (rat) paired with LC-MS analysis have been exploited to evaluate in vivo toxicology, pharmacokinetics, and distribution. Results : Our research highlights the low in vivo toxicity profile of BM1, its affinity for the renal system in rats and its good absorption, distribution, metabolism, and excretion (ADME) features. Our compound preserves a potent activity also against azole-resistant fungal strains, including C. auris isolates and CDR6-overexpressing strains. Conclusions : We confirmed low MICs against several Candida species, including preliminary data versus C. auris. The good ADME and biochemical characteristics make BM1 suitable and safe for daily administration and particularly indicated to treat renal infections. These data make BM1 and its derivatives a novel promising antifungal class. |
| Databáze: | OpenAIRE |
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