Abstract
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.
Highlights
Antimicrobial resistance (AMR) represents a complex global health challenge due to its natural insurgence and rapid spread caused by the use and misuse of antimicrobial agents in humans and animals [1,2,3,4]
We have recently developed two common-features pharmacophore models for NorA Efflux pump inhibitors (EPIs), which allowed the identification of FDA-approved drugs endowed with potent inhibitory activity [35]
It should be noted that many quinoline derivatives were used to develop and validate the pharmacophore hypothesis, underlining an important role of the protonable moieties located in position 4 of the quinoline scaffold, with the ethyl-N,N-diethylamine and 1-ethylpiperidine groups being generally associated with the most interesting results in terms of EPI activity and physico-chemical properties
Summary
Antimicrobial resistance (AMR) represents a complex global health challenge due to its natural insurgence and rapid spread caused by the use and misuse of antimicrobial agents in humans and animals [1,2,3,4]. Recent reports estimate that if no action is taken, by 2050 AMR will cause up to 10 million annual deaths globally [6,7]. A long-term strategy to overcome the early insurgence of AMR has necessarily to turn the attention on novel chemical scaffolds acting with new mechanisms of action. Since microorganisms mainly evolve resistance only for compounds exerting bactericidal or bacteriostatic effects, the lack of the antimicrobial activity of ARBs seems to be a strength for their potential use [13]
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