Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: Study of 6-substituted pyridine-3-boronic acid derivatives

Fontaine, Fanny; Héquet, Arnaud; Voisin‐Chiret, Anne Sophie; Bouillon, Alexandre; Lesnard, Aurélien; Cresteil, Thierry; Jolivalt, Claude; Rault, Syl­vain

doi:10.1016/j.ejmech.2015.02.056

Cited by 47 publications

(26 citation statements)

References 57 publications

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“…Moreover, they did not inhibit the mammalian P‐gp efflux pump and 39 (Figure ) showed a low level of toxicity in KB cells at 10 µM. However, they were still less effective than the positive control, reserpine . In addition, boronic acids are also considered as potent β‐lactamase inhibitors and possess a variety of other biological effects .…”

Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 99%

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Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

136

116

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Bacterial infections are an increasingly serious issue worldwide. The inability of existing therapies to treat multidrug‐resistant pathogens has been recognized as an important challenge of the 21st century. Efflux pumps are important in both intrinsic and acquired bacterial resistance and identification of small molecule efflux pump inhibitors (EPIs), capable of restoring the effectiveness of available antibiotics, is an active research field. In the last two decades, much effort has been made to identify novel EPIs. However, none of them has so far been approved for therapeutic use. In this article, we explore different structural families of currently known EPIs for multidrug resistance efflux systems in the most extensively studied pathogens (NorA in Staphylococcus aureus, AcrAB‐TolC in Escherichia coli, and MexAB‐OprM in Pseudomonas aeruginosa). Both synthetic and natural compounds are described, with structure‐activity relationship studies and optimization processes presented systematically for each family individually. In vitro activities against selected test strains are presented in a unifying manner for all the EPIs described, together with the most important toxicity, pharmacokinetic and in vivo efficacy data. A critical evaluation of lead‐likeness characteristics and the potential for clinical development of the most promising inhibitors of the three efflux systems is described. This overview of EPIs is a good starting point for the identification of novel effective antibacterial drugs.

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Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 99%

“…positive control, reserpine. 206 In addition, boronic acids are also considered as potent β-lactamase inhibitors and possess a variety of other biological effects. 120,207 Thus, selectivity for efflux pumps should be addressed in the future development of this class of EPIs.…”

mentioning

confidence: 99%

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

136

116

View full text Add to dashboard Cite

show abstract

“…In addition to overexpression of β-lactamases in bacteria, another known resistance mechanism is related to efflux pumps, thus the discovery and design of novel antibacterial drugs that could act by inhibiting the action of these pumps is an exciting approach [ 67 , 68 ]. It has been recognized that boronic acid derivatives can be promising inhibitors of chromosomal NorA efflux pump of Staphylococcus aureus .…”

Section: Synthesis and Biological Applications Of Boronic Acids Dementioning

confidence: 99%

“…It has been recognized that boronic acid derivatives can be promising inhibitors of chromosomal NorA efflux pump of Staphylococcus aureus . These pumps are involved in bacterial resistance to the antibacterial fluoroquinolones, specially to hydrophobic fluoroquinolones such as ciprofloxacin [ 67 ]. Synthetic inhibitors of efflux pumps are usually based on heterocyclic compounds and in pump efflux inhibition assays often use the alkaloid reserpine as a positive control, but this alkaloid is not used in therapy due to neurotoxicity at therapeutic concentrations (minimum modulatory concentration (MMC) of 4–8 µg/mL).…”

Section: Synthesis and Biological Applications Of Boronic Acids Dementioning

confidence: 99%

Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications

et al. 2020

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Boron containing compounds have not been widely studied in Medicinal Chemistry, mainly due to the idea that this group could confer some toxicity. Nowadays, this concept has been demystified and, especially after the discovery of the drug bortezomib, the interest for these compounds, mainly boronic acids, has been growing. In this review, several activities of boronic acids, such as anticancer, antibacterial, antiviral activity, and even their application as sensors and delivery systems are addressed. The synthetic processes used to obtain these active compounds are also referred. Noteworthy, the molecular modification by the introduction of boronic acid group to bioactive molecules has shown to modify selectivity, physicochemical, and pharmacokinetic characteristics, with the improvement of the already existing activities. Besides, the preparation of compounds with this chemical group is relatively simple and well known. Taking into consideration these findings, this review reinforces the relevance of extending the studies with boronic acids in Medicinal Chemistry, in order to obtain new promising drugs shortly.

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“…Therefore, there is an urgent need to develop and identify potent efflux pump inhibitors (EPIs; Handzlik et al 2013). The combination of an EPI and the antibiotic is the strategy, which prevents efflux of antibiotic and recovers its intracellular concentration (Fontaine et al 2015). Alternatively, these compounds can act as regulators of efflux systems, namely as EPIs to block the activity of drug efflux pumps (Pages & Amaral 2009).…”

Section: Introductionmentioning

confidence: 99%

Efflux pump inhibitory activity of flavonoids isolated from Alpinia calcarata against methicillin-resistant Staphylococcus aureus

et al. 2016

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Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium responsible for several infections in humans. The infections caused by this bacterial strain are difficult to treat due to the resistance of MRSA to clinically used antibiotics. Several medicinal plants extracts and their phytoconstituents have been reported to possess modulation and efflux pump inhibitory (EPI) activity against MRSA strains. Alpinia calcarata rhizomes have been reported to be used in Ayurveda for several ailments including fungal infections. Based on this information and in continuation with our efforts to discover EPIs from Indian medicinal plants, we describe EPI activity of flavonoids isolated from A. calcarata. Galangin and kaempferol showed ≥ 32-fold modulation in minimum inhibitory concentration (MIC) of ethidium bromide (EtBr) as well as norfloxacin in NorA-overexpressed S. aureus (SA-1199B) strain. Pinocembrin showed 32-fold modulation of EtBr MIC in SA-1199 strain, but not in SA-1199B and K1758 strains. A significant difference was not observed in the modulation of norfloxacin MIC by galangin in SA-1199 and SA-1199B strains, which may be due to non-specific nature of galangin as modulator or EPI. However, kaempferol modulated the MIC of EtBr as well as norfloxacin 64-fold and 32-fold, respectively. Also, the best modulatory effect of kaempferol was observed only in SA-1199B strain compared to two other strains. The EPI activity of kaempferol and galangin were found to be competitive with respect to verapamil. In dose-response assay, kaempferol at 31.25 µg/mL concentration was found to be better EPI by inhibiting NorA pump in SA-1199B strain and also demonstrated further confocal microscopy.

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Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: Study of 6-substituted pyridine-3-boronic acid derivatives

Cited by 47 publications

References 57 publications

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Boronic Acids and Their Derivatives in Medicinal Chemistry: Synthesis and Biological Applications

Efflux pump inhibitory activity of flavonoids isolated from Alpinia calcarata against methicillin-resistant Staphylococcus aureus

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