Transfer of Cationic Antibacterial Agents Berberine, Palmatine, and Benzalkonium Through Bimolecular Planar Phospholipid Film and Staphylococcus aureus Membrane

Severina, Inna I.; Muntyan, Maria S.; Lewis, Kim; Vp, Skulachev

doi:10.1080/152165401317291183

Cited by 67 publications

(42 citation statements)

References 13 publications

(15 reference statements)

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“…The present study observed that IMP significantly increased the intracellular BBR fluorescence. BER has also been reported to exert its effects via targeting the cytoplasmic membrane and intra-nuclear DNA (18,29). Collectively, based on the present results, it may be speculated that IMP had synergistic effects with BEB via increasing the accumulation of BEB in the intracellular space of P. aeruginosa cells.…”

Section: Discussionmentioning

confidence: 58%

Berberine inhibits the MexXY‑OprM efflux pump to reverse imipenem resistance in a clinical carbapenem‑resistant Pseudomonas aeruginosa isolate in a planktonic state

Fen

Wang

2017

Exp Ther Med

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Abstract. Pseudomonas (P.) aeruginosa is an ubiquitous and metabolically versatile opportunistic pathogen and may cause various life-threatening diseases. Due to increasing emergence of resistance to carbapenems, novel drugs with improved antibacterial activities compared with those of traditional antibiotics are required. In the present study, berberine (BEB), a natural isoquinoline alkaloid, was used in combination with imipenem (IMP), a commonly-used carbapenem, to investigate their antibacterial activities against a clinical P. aeruginosa isolate PA012 and the potential mechanism. Screening revealed that the minimum inhibitory concentrations (MICs) of BEB and IMP were 512 and 256 µg/ml, respectively. The combination of BEB (1/4 MIC) and IMP (1/8 MIC) exhibited a synergistic effect with a fractional inhibitory concentration index of 0.375. The synergism of BEB and IMP was also demonstrated in a time-kill test and by scanning electron microscopic observation. Treatment with BEB at ¼ MIC in combination with IMP at 1/16, 1/8, 1/4 and ½ MIC revealed a concentration-dependent promoting effect of IMP on the intracellular accumulation of BEB and inhibition of bacterial adhesion. Further analysis of gene expression revealed that BEB (1/4 MIC) combined with IMP (1/8 MIC) decreased MexZ, MexX, MexY and outer membrane protein (Opr)M by 38, 35, 46 and 49% in PA012. In conclusion, these results suggested that IMP had synergistic effects with BEB against the clinical isolate PA012 via inhibition of the MexXY-OprM efflux pump.

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Section: Discussionmentioning

confidence: 58%

Berberine inhibits the MexXY‑OprM efflux pump to reverse imipenem resistance in a clinical carbapenem‑resistant Pseudomonas aeruginosa isolate in a planktonic state

Fen

Wang

2017

Exp Ther Med

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“…We found that Berberis plants produce 5Ј-MHC-D, which completely blocked NorA and acted in synergy with berberine (45,46). In the absence of efflux, berberine, a hydrophobic cation, accumulates in the cells of microbial pathogens, and the accumulation is driven by the membrane potential (41). Active accumulation in the pathogen is an at- tractive property for an antimicrobial, and berberine inspired the design of a cationic polymer with a "sterile" surface (47) that is not subject to MDR-dependent resistance (30).…”

Section: Discussionmentioning

confidence: 99%

Multidrug Pump Inhibitors Uncover Remarkable Activity of Plant Antimicrobials

Tegos

Stermitz

Lomovskaya

et al. 2002

Antimicrob Agents Chemother

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423

317

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Plant antimicrobials are not used as systemic antibiotics at present. The main reason for this is their low level of activity, especially against gram-negative bacteria. The reported MIC is often in the range of 100 to 1,000 g/ml, orders of magnitude higher than those of common broad-spectrum antibiotics from bacteria or fungi. Major plant pathogens belong to the gram-negative bacteria, which makes the low level of activity of plant antimicrobials against this group of microorganisms puzzling. Gram-negative bacteria have an effective permeability barrier, comprised of the outer membrane, which restricts the penetration of amphipathic compounds, and multidrug resistance pumps (MDRs), which extrude toxins across this barrier. It is possible that the apparent ineffectiveness of plant antimicrobials is largely due to the permeability barrier. We tested this hypothesis in the present study by applying a combination of MDR mutants and MDR inhibitors. A panel of plant antimicrobials was tested by using a set of bacteria representing the main groups of plant pathogens. The human pathogens Pseudomonas aeruginosa, Escherichia coli, and Salmonella enterica serovar Typhimurium were also tested. The results show that the activities of the majority of plant antimicrobials were considerably greater against the gram-positive bacteria Staphylococcus aureus and Bacillus megaterium and that disabling of the MDRs in gram-negative species leads to a striking increase in antimicrobial activity. Thus, the activity of rhein, the principal antimicrobial from rhubarb, was potentiated 100-to 2,000-fold (depending on the bacterial species) by disabling the MDRs. Comparable potentiation of activity was observed with plumbagin, resveratrol, gossypol, coumestrol, and berberine. Direct measurement of the uptake of berberine, a model plant antimicrobial, confirmed that disabling of the MDRs strongly increases the level of penetration of berberine into the cells of gram-negative bacteria. These results suggest that plants might have developed means of delivering their antimicrobials into bacterial cells. These findings also suggest that plant antimicrobials might be developed into effective, broad-spectrum antibiotics in combination with inhibitors of MDRs.

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“…Cationic compounds such as ethidium are electrophoretically imported into energized bacterial cells, and this process is driven by the ⌬ (inside negative). Consequently, significant levels of accumulation of cationic compounds can occur even in the absence of an active uptake system (20,21). Binding of ethidium to the cellular polynucleotides can further contribute to drug accumulation in cells relative to the environment.…”

Section: Figmentioning

confidence: 99%

Facilitated Drug Influx by an Energy-uncoupled Secondary Multidrug Transporter

Mazurkiewicz

Poelarends²,

Driessen

et al. 2004

Journal of Biological Chemistry

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The majority of bacterial multidrug resistance transporters belong to the class of secondary transporters. LmrP is a proton/drug antiporter of Lactococcus lactis that extrudes positively charged lipophilic substrates from the inner leaflet of the membrane to the external medium. This study shows that LmrP is a true secondary transporter. In the absence of a proton motive force, LmrP facilitates downhill fluxes of ethidium in both directions. These fluxes are inhibited by other substrates of LmrP. The cysteine-reactive agent p-chloromercuri-benzene sulfonate inhibits these fluxes in wild type LmrP but not in the cysteine-less LmrP C270A mutant. Cysteine mutagenesis of LmrP resulted in three mutants, D68C/C270A, D128C/C270A, and E327C/C270A, with an energy-uncoupled phenotype. Asp 68 is located in the conserved motif GXXX(D/E)(R/K)XGRK for the major facilitator superfamily of secondary transporters and was found to play an important role in energy coupling, whereas the negatively charged residues Asp 128 and Glu 327 have indirect effects on the transport process. L. lactis strains expressing these uncoupled mutants of LmrP show an increased rate of ethidium influx and an increased drug susceptibility compared with cells harboring an empty vector. The rate of influx in these mutants is enhanced by a transmembrane electrical potential, inside negative. These observations suggest a new strategy for eliminating drug-resistant microbial pathogens, i.e. the design and use of modulators of secondary multidrug resistance transporters that uncouple drug efflux from proton influx, thereby allowing transmembrane electrical potential-driven influx of cationic drugs.

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Transfer of Cationic Antibacterial Agents Berberine, Palmatine, and Benzalkonium Through Bimolecular Planar Phospholipid Film and Staphylococcus aureus Membrane

Cited by 67 publications

References 13 publications

Berberine inhibits the MexXY‑OprM efflux pump to reverse imipenem resistance in a clinical carbapenem‑resistant Pseudomonas aeruginosa isolate in a planktonic state

Berberine inhibits the MexXY‑OprM efflux pump to reverse imipenem resistance in a clinical carbapenem‑resistant Pseudomonas aeruginosa isolate in a planktonic state

Multidrug Pump Inhibitors Uncover Remarkable Activity of Plant Antimicrobials

Facilitated Drug Influx by an Energy-uncoupled Secondary Multidrug Transporter

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