New C-6 functionalized quinoline NorA inhibitors strongly synergize with ciprofloxacin against planktonic and biofilm growing resistant Staphylococcus aureus strains
| Autor: | Tommaso Felicetti, Nicholas Cedraro, Andrea Astolfi, Giada Cernicchi, Gianmarco Mangiaterra, Salvatore Vaiasicca, Serena Massari, Giuseppe Manfroni, Maria Letizia Barreca, Oriana Tabarrini, Francesca Biavasco, Violetta Cecchetti, Carla Vignaroli, Stefano Sabatini |
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| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Efflux pump inhibitors Methicillin-Resistant Staphylococcus aureus Staphylococcus aureus Antibiotic resistance breakers Antimicrobial resistance Biofilm NorA Organic Chemistry General Medicine Microbial Sensitivity Tests Staphylococcal Infections Plankton Anti-Bacterial Agents NorA Efflux pump inhibitors BiofilmAntimicrobial resistance Staphylococcus aureus Antibiotic resistance breakers Bacterial Proteins Ciprofloxacin Biofilms Drug Discovery Humans BiofilmAntimicrobial resistance Multidrug Resistance-Associated Proteins |
| Zdroj: | European journal of medicinal chemistry. 241 |
| ISSN: | 1768-3254 |
| Popis: | Antimicrobial resistance (AMR) represents a global health issue threatening our social lifestyle and the world economy. Efflux pumps are widely involved in AMR by playing a primary role in the development of specific mechanisms of resistance. In addition, they seem to be involved in the process of biofilm formation and maintenance, contributing to enhance the risk of creating superbugs difficult to treat. Accordingly, the identification of non-antibiotic molecules able to block efflux pumps, namely efflux pump inhibitors (EPIs), could be a promising strategy to counteract AMR and restore the antimicrobial activity of ineffective antibiotics. Herein, we enlarge the knowledge about the structure-activity relationship of 2-phenylquinoline Staphylococcus aureus NorA EPIs by reporting a new series of very potent C-6 functionalized derivatives. Best compounds significantly inhibited ethidium bromide efflux in a NorA-overexpressing S. aureus strain (SA-1199B) and strongly synergized at very low concentrations (0.20-0.78 μg/mL) with ciprofloxacin (CPX) against CPX-resistant S. aureus strains (SA-1199B and SA-K2378), as proved by checkerboard and time-kill experiments. In addition, some of these EPIs (9b and 10a) produced a post-antibiotic effect of 1.2 h and strongly enhanced antibiofilm activity of CPX against SA-1199B strain. Interestingly, at the concentrations used to reach synergy with CPX against resistant S. aureus strains, most of the EPI compounds did not show any human cell toxicity. Finally, by exploiting the recent released crystal structure of NorA, we observed that best EPI 9b highlighted a favourable docking pose, establishing some interesting interactions with key residues. |
| Databáze: | OpenAIRE |
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