Abstract
NorA is the most studied efflux pump of Staphylococcus aureus and is responsible for high level resistance towards fluoroquinolone drugs. Although along the years many NorA efflux pump inhibitors (EPIs) have been reported, poor information is available about structure-activity relationship (SAR) around their nuclei and reliability of data supported by robust assays proving NorA inhibition. In this regard, we focussed efforts on the 2-phenylquinoline as a promising chemotype to develop potent NorA EPIs. Herein, we report SAR studies about the introduction of different aryl moieties on the quinoline C-2 position. The new derivative 37a showed an improved EPI activity (16-fold) with respect to the starting hit 1. Moreover, compound 37a exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (norA+). Also, 37a exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of “selectivity index” in comparison to 1.
Highlights
Antimicrobial resistance (AMR) is a complex threat for human health and represents a hot topic in drug discovery[1]
Amongst the wide range of resistance mechanisms developed by bacteria, one of the most common is the drug extrusion from the cell, which can reduce intracellular drugs to sub-inhibitory concentrations allowing bacteria to grow in the presence of routinely adopted therapeutic doses[7]
In order to identify new potent efflux pump inhibitors (EPIs) to counteract the rapid insurgence of bacterial resistance towards common antibiotics, we made a further effort to build a robust structure-activity relationship (SAR) delineation around the quinoline-based NorA inhibitors
Summary
Antimicrobial resistance (AMR) is a complex threat for human health and represents a hot topic in drug discovery[1]. Considering the microbial promptness in achieving successful machinery escaping antibiotic activity towards new drugs[3,4], the use of non-antibiotic adjuvant molecules targeting resistance mechanisms, in co-administration with antibacterials, is a valid approach to recover drug sensitivity in resistant strains[5,6]. The fascinating idea to “freeze” resistance would allow antibiotics, for which resistance occurred, to recover their activity thereby renewing our armamentarium to fight microbial infections. For some drugs, microorganisms can only acquire resistance in the presence of efflux pump activity. Efflux pumps play a non-specific role in the early stages of antibiotic exposure, thereby allowing microorganisms to develop more specific and effective mechanisms of resistance[4,8,9]. The use of efflux pump inhibitors (EPIs) in combination with extruded drugs may be a major strategy in the development of effective antimicrobial treatments. Little has been done in terms of EPI development and no inhibitors have ever reached the clinical use[10]
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