3-Arylpiperidines as potentiators of existing antibacterial agents

Thorarensen, Atli; Presley-Bodnar, Alice L; Marotti, Keith R.; Boyle, Timothy P.; Heckaman, Charlotte L.; Bohanon, Michael J.; Tomich, Paul K.; Zurenko, Gary E.; Sweeney, Michael T.; Yagi, Betty H.

doi:10.1016/s0960-894x(01)00330-4

Cited by 48 publications

(19 citation statements)

References 21 publications

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“…The up-regulation of efflux systems through physiological induction and spontaneous mutation can significantly lower the intracellular concentration of many antibiotics, causing an impact on clinical efficacy. For this reason, many academic and pharmaceutical programs have focused on identifying inhibitors of gram-negative and gram-positive efflux systems that could potentially be used in combination with antibiotics to improve efficacy and suppress resistance (1,2,3,8,10,21,31,34). In vitro, EPIs have been shown to reduce spontaneous resistance frequencies to antibiotics in P. aeruginosa (19), S. pneumoniae (20), and S. aureus (21,22).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Antibiotic Efflux in Bacteria by the Novel Multidrug Resistance Inhibitors Biricodar (VX-710) and Timcodar (VX-853)

Mullin

Mani

Grossman

2004

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 99%

Inhibition of Antibiotic Efflux in Bacteria by the Novel Multidrug Resistance Inhibitors Biricodar (VX-710) and Timcodar (VX-853)

Mullin

Mani

Grossman

2004

Antimicrob Agents Chemother

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“…To combat MDR, efflux pump inhibitors (EPIs) are an attractive option, and several EPIs that act against the AcrAB-TolC efflux pump have already been described in the literature (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), among which arylpiperazine and arylmorpholine derivatives constitute some of the largest systematically examined compound classes.…”

mentioning

confidence: 99%

Novel Piperazine Arylideneimidazolones Inhibit the AcrAB-TolC Pump in Escherichia coli and Simultaneously Act as Fluorescent Membrane Probes in a Combined Real-Time Influx and Efflux Assay

Bohnert

Schuster²,

Kern³

et al. 2016

Antimicrob Agents Chemother

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In this study, we tested five compounds belonging to a novel series of piperazine arylideneimidazolones for the ability to inhibit the AcrAB-TolC efflux pump. The biphenylmethylene derivative (BM-19) and the fluorenylmethylene derivative (BM-38) were found to possess the strongest efflux pump inhibitor (EPI) activities in the AcrAB-TolC-overproducing Escherichia coli strain 3-AG100, whereas BM-9, BM-27, and BM-36 had no activity at concentrations of up to 50 M in a Nile red efflux assay. MIC microdilution assays demonstrated that BM-19 at 1/4 MIC (intrinsic MIC, 200 M) was able to reduce the MICs of levofloxacin, oxacillin, linezolid, and clarithromycin 8-fold. BM-38 at 1/4 MIC (intrinsic MIC, 100 M) was able to reduce only the MICs of oxacillin and linezolid (2-fold). Both compounds markedly reduced the MIC of rifampin (BM-19, 32-fold; and BM-38, 4-fold), which is suggestive of permeabilization of the outer membrane as an additional mechanism of action. Nitrocefin hydrolysis assays demonstrated that in addition to their EPI activity, both compounds were in fact weak permeabilizers of the outer membrane. Moreover, it was found that BM-19, BM-27, BM-36, and BM-38 acted as near-infrared-emitting fluorescent membrane probes, which allowed for their use in a combined influx and efflux assay and thus for tracking of the transport of an EPI across the outer membrane by an efflux pump in real time. The EPIs BM-38 and BM-19 displayed the most rapid influx of all compounds, whereas BM-27, which did not act as an EPI, showed the slowest influx.

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“…Among gram-negative bacteria, many of these MDR efflux pumps belong to the RND (resistance-nodulation-cell division) type family of tripartite efflux pumps. MDR in selected gram-negative bacteria has been shown to be reversible by using compounds like Phe-Arg-␤-naphthylamide (PA␤N) or other small N-heterocyclic organic compounds thought to inhibit RND type efflux pump activity through unknown mechanisms (4,5,7,9). In this study, we describe another novel type of putative efflux pump inhibitor (EPI) identified through screening of an N-heterocyclic organic compound library for MDR reversal activity in Escherichia coli.…”

mentioning

confidence: 99%

Selected Arylpiperazines Are Capable of Reversing Multidrug Resistance in Escherichia coli Overexpressing RND Efflux Pumps

Bohnert

Kern

2005

Antimicrob Agents Chemother

196

143

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Several arylpiperazines capable of reversing multidrug resistance (MDR) in Escherichia coli overexpressing acrAB and acrEF but not in pump-deficient mutant strains were identified. 1-(1-Naphthylmethyl)-piperazine, one of the more active compounds, enhanced susceptibility to fluoroquinolones and other agents and increased the intracellular concentration of levofloxacin and ethidium bromide, suggesting efflux pump inhibition as the mechanism of MDR reversal.

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3-Arylpiperidines as potentiators of existing antibacterial agents

Cited by 48 publications

References 21 publications

Inhibition of Antibiotic Efflux in Bacteria by the Novel Multidrug Resistance Inhibitors Biricodar (VX-710) and Timcodar (VX-853)

Inhibition of Antibiotic Efflux in Bacteria by the Novel Multidrug Resistance Inhibitors Biricodar (VX-710) and Timcodar (VX-853)

Novel Piperazine Arylideneimidazolones Inhibit the AcrAB-TolC Pump in Escherichia coli and Simultaneously Act as Fluorescent Membrane Probes in a Combined Real-Time Influx and Efflux Assay

Selected Arylpiperazines Are Capable of Reversing Multidrug Resistance in Escherichia coli Overexpressing RND Efflux Pumps

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