Secondary multidrug efflux pump mutants alter Escherichia coli biofilm growth in the presence of cationic antimicrobial compounds

Bay, Denice C.; Stremick, Carol A.; Slipski, Carmine J.; Turner, Raymond J.

doi:10.1016/j.resmic.2016.11.003

Cited by 67 publications

(56 citation statements)

References 56 publications

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“…In addition, the EPI also potentiated antibacterial AcrAB substrates in a range of other Enterobacteriaceae pathogens including K. pneumoniae and Shigella flexneri among others [84]. Similar to D13-9001, computational study indicated the presence of interaction of the EPI with the same "hydrophobic trap" of the AcrB pump, with the pyridine ring forming sterically-hindered ring-stacking interactions [85].…”

Section: Epis and Their Potential Role In Biofilm Disruption In E Colimentioning

confidence: 78%

“…The anti-malarial drug, artesunate has been reported to enhance the antimicrobial effect of β-lactam drugs against E. coli, through the suppression of AcrAB-TolC efflux [91]. indicated the presence of interaction of the EPI with the same "hydrophobic trap" of the AcrB pump, with the pyridine ring forming sterically-hindered ring-stacking interactions [85]. Zeng et al [86] developed synthetic indole derivatives, based on the TolC structure in an attempt to inhibit the AcrAB-TolC pump.…”

Section: Epis and Their Potential Role In Biofilm Disruption In E Colimentioning

confidence: 99%

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Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

2019

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Antibiotic resistance represents a significant threat to the modern healthcare provision. The ESKAPEE pathogens (Enterococcus faecium., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli), in particular, have proven to be especially challenging to treat, due to their intrinsic and acquired ability to rapidly develop resistance mechanisms in response to environmental threats. The development of biofilm has been characterised as an essential contributing factor towards antimicrobial-resistance and tolerance. Several studies have implicated the involvement of efflux pumps in antibiotic resistance, both directly, via drug extrusion and indirectly, through the formation of biofilm. As a result, the underlying mechanism of these pumps has attracted considerable interest due to the potential of targeting these protein structures and developing novel adjunct therapies. Subsequent investigations have revealed the ability of efflux pump-inhibitors (EPIs) to block drug-extrusion and disrupt biofilm formation, thereby, potentiating antibiotics and reversing resistance of pathogen towards them. This review will discuss the potential of EPIs as a possible solution to antimicrobial resistance, examining different challenges to the design of these compounds, with an emphasis on Gram-negative ESKAPEE pathogens.

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Section: Epis and Their Potential Role In Biofilm Disruption In E Colimentioning

confidence: 78%

Section: Epis and Their Potential Role In Biofilm Disruption In E Colimentioning

confidence: 99%

Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

2019

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“…It has been reported that genetically disrupting any of the MDR efflux systems in Salmonella Typhimurium , or chemical inactivation of MDR efflux using EIs repressed biofilm formation ( Baugh et al, 2012 ). Deletions of multipartite efflux system genes acrB, acrE , and tolC of E. coli also resulted in significant reductions in biofilm growth ( Bay et al, 2016 ). However, loss of secondary active multidrug resistance transporters that confer overlapping substrate resistance to a broad range of antimicrobials led to similar or enhanced biofilm formation of E. coli ( Bay et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of an Efflux Transporter LmrB Regulating Stress Response and Extracellular Polysaccharide Synthesis in Streptococcus mutans

et al. 2017

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Efflux transporters have been implicated in regulating bacterial virulence properties such as resistance to antibiotics, biofilm formation and colonization. The pathogenicity of Streptococcus mutans, the primary etiologic agent of human dental caries, relies on the bacterium’s ability to form biofilms on tooth surface. However, the studies on efflux transporters in S. mutans are scare and the function of these transporters remained to be clarified. In this study, we identified an efflux transporter (LmrB) in S. mutans through cloning the lmrB gene into Escherichia coli. Introducing lmrB into E. coli conferred a multidrug-resistant phenotype and resulted in higher EtBr efflux activity which could be suppressed by efflux inhibitor. To explore whether LmrB was involved in S. mutans virulence properties regulation, we constructed the lmrB inactivation mutant and examined the phenotypes of the mutant. It was found that LmrB deficiency resulted in increased IPS storage and prolonged acid production. Enhanced biofilm formation characterized by increased extracellular polysaccharides (EPS) production and elevated resistance to hydrogen peroxide and antimicrobials were also observed in lmrB mutant. To gain a better understanding of the global role of LmrB, a transcriptome analysis was performed using lmrB mutant strain. The expression of 107 genes was up- or down-regulated in the lmrB mutant compared with the wild type. Notably, expression of genes in several genomic islands was differentially modulated, such as stress-related GroELS and scnRK, sugar metabolism associated glg operons and msmREFGK transporter. The results presented here indicate that LmrB plays a vital global role in the regulation of several important virulence properties in S. mutans.

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“…Obviously it is entirely reasonable that this might serve, when active, to remove a cation such as diS-C3(5), and the fact that the potent effluxers mdtI and mdtJ are also spermi(di)ne effluxers (Table 1) lends weight to this view. In a similar vein, the KOs of mdtH and mdtK [140] have a significantly reduced uptake; although they were originally tagged as effluxers (in the sense of multidrug transporters), it seems more likely that they are in fact antiporters, normally contributing to the uptake (here) of the cyanine dye.…”

Section: Variation Of the Uptake Of A Lipophilic Carbocyanine Cationmentioning

confidence: 95%

Involvement of multiple influx and efflux transporters in the accumulation of cationic fluorescent dyes byEscherichia coli

Jindal¹,

Yang

Day

et al. 2019

Preprint

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We used high-throughput flow cytometry to assess the ability of individual gene knockout strains ofE colito take up two membrane-permeable, cationic fluorescent dyes, viz the carbocyanine diS-C3(5) and the DNA dye SYBR Green. Individual strains showed a large range of distributions of uptake. The range of modal steady-state uptakes for the carbocyanine between the different strains was 36-fold. Knockouts of the ATP synthase α- and β-subunits greatly inhibited uptake, implying that most uptake was ATP-driven rather than being driven by say a membrane potential. Dozens of transporters changed the steady-state uptake of the dye by more than 50% with respect to that of the wild type, in both directions (increased or decreased); knockouts in known influx and efflux transporters behaved as expected, giving confidence in the general strategy. Many of the knockouts with the most reduced uptake were transporter genes of unknown function (‘y-genes’). Similarly, several overexpression variants in the ‘ASKA’ collection had the anticipated, opposite effects. Similar findings were made with SYBR Green (the range being some 69-fold), though despite it too containing a benzimidazole motif there was negligible correlation between its uptake and that of the carbocyanine when compared across the various strains. Overall, we conclude that the uptake of these dyes may be catalysed by a great many transporters of possibly broad and presently unknown specificity. This casts serious doubt upon the use of such dyes as quantitative stains for representing either bioenergetic parameters or the amount of cellular DNA in unfixed cells (in vivo). By contrast, it opens up their potential use as transporter assay substrates in high-throughput screening.

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Secondary multidrug efflux pump mutants alter Escherichia coli biofilm growth in the presence of cationic antimicrobial compounds

Cited by 67 publications

References 56 publications

Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

Effectiveness of Efflux Pump Inhibitors as Biofilm Disruptors and Resistance Breakers in Gram-Negative (ESKAPEE) Bacteria

Identification of an Efflux Transporter LmrB Regulating Stress Response and Extracellular Polysaccharide Synthesis in Streptococcus mutans

Involvement of multiple influx and efflux transporters in the accumulation of cationic fluorescent dyes byEscherichia coli

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