scholarly journals From quinoline to quinazoline‐based S. aureus NorA efflux pump inhibitors by coupling focused scaffold hopping approach and pharmacophore search

ChemMedChem ◽  
2021 ◽  
Author(s):  
Nicholas Cedraro ◽  
Rolando Cannalire ◽  
Andrea Astolfi ◽  
Gianmarco Mangiaterra ◽  
Tommaso Felicetti ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Scaffold Hopping ◽  
Efflux Pump Inhibitors

scholarly journals Structural Modifications of the Quinolin-4-yloxy Core to Obtain New Staphylococcus aureus NorA Inhibitors

2020 ◽  
Vol 21 (19) ◽  
pp. 7037
Author(s):  
Rolando Cannalire ◽  
Gianmarco Mangiaterra ◽  
Tommaso Felicetti ◽  
Andrea Astolfi ◽  
Nicholas Cedraro ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Efflux Pump ◽  
A549 Cells ◽  
Scaffold Hopping ◽  
Inhibition Activity ◽  
Structural Modifications ◽  
Efflux Pump Inhibitors ◽  
New Compounds ◽  
Pharmacophore Models

Tackling antimicrobial resistance (AMR) represents a social responsibility aimed at renewing the antimicrobial armamentarium and identifying novel therapeutical approaches. Among the possible strategies, efflux pumps inhibition offers the advantage to contrast the resistance against all drugs which can be extruded. Efflux pump inhibitors (EPIs) are molecules devoid of any antimicrobial activity, but synergizing with pumps-substrate antibiotics. Herein, we performed an in silico scaffold hopping approach starting from quinolin-4-yloxy-based Staphylococcus aureus NorA EPIs by using previously built pharmacophore models for NorA inhibition activity. Four scaffolds were identified, synthesized, and modified with appropriate substituents to obtain new compounds, that were evaluated for their ability to inhibit NorA and synergize with the fluoroquinolone ciprofloxacin against resistant S. aureus strains. The two quinoline-4-carboxamide derivatives 3a and 3b showed the best results being synergic (4-fold MIC reduction) with ciprofloxacin at concentrations as low as 3.13 and 1.56 µg/mL, respectively, which were nontoxic for human THP-1 and A549 cells. The NorA inhibition was confirmed by SA-1199B ethidium bromide efflux and checkerboard assays against the isogenic pair SA-K2378 (norA++)/SA-K1902 (norA-). These in vitro results indicate the two compounds as valuable structures for designing novel S. aureus NorA inhibitors to be used in association with fluoroquinolones.

Screening of Natural Products and Derivatives for the Identification of RND Efflux Pump Inhibitors

2016 ◽  
Vol 19 (9) ◽  
pp. 705-713 ◽  
Author(s):  
Debarati Choudhury ◽  
Anupam Talukdar ◽  
Pankaj Chetia ◽  
Amitabha Bhattacharjee ◽  
Manabendra Choudhury
Keyword(s):  
Natural Products ◽  
Efflux Pump ◽  
Rnd Efflux Pump ◽  
Efflux Pump Inhibitors

Virtual Screening for Novel Staphylococcus Aureus NorA Efflux Pump Inhibitors From Natural Products

2015 ◽  
Vol 11 (2) ◽  
pp. 135-155 ◽  
Author(s):  
Khac-Minh Thai ◽  
Trieu-Du Ngo ◽  
Thien-Vy Phan ◽  
Thanh-Dao Tran ◽  
Ngoc-Vinh Nguyen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Natural Products ◽  
Virtual Screening ◽  
Efflux Pump ◽  
Efflux Pump Inhibitors

scholarly journals Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation

2013 ◽  
Vol 7 (1) ◽  
pp. 34-52 ◽  
Author(s):  
Christina Kourtesi ◽  
Anthony R Ball ◽  
Ying-Ying Huang ◽  
Sanjay M Jachak ◽  
D Mariano A Vera ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Major Theme ◽  
Clinical Implementation ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Development Path ◽  
Microbial Infections ◽  
Efflux Pump Inhibitors ◽  
Shed Light

Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches.

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