scholarly journals Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Escherichia coli

2005 ◽  
Vol 57 (2) ◽  
pp. 339-343 ◽  
Author(s):  
Winfried V. Kern ◽  
Petra Steinke ◽  
Anja Schumacher ◽  
Sabine Schuster ◽  
Heike von Baum ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Drug Susceptibility ◽  
Antimicrobial Drug ◽  
Clinical Isolates ◽  
Efflux Pump Inhibitor

scholarly journals oqxAB Encoding a Multidrug Efflux Pump in Human Clinical Isolates of Enterobacteriaceae

2009 ◽  
Vol 53 (8) ◽  
pp. 3582-3584 ◽  
Author(s):  
Hong Bin Kim ◽  
Minghua Wang ◽  
Chi Hye Park ◽  
Eui-Chong Kim ◽  
George A. Jacoby ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Efflux Pump ◽  
Clinical Isolates ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump

ABSTRACT The genes for multidrug efflux pump OqxAB, which is active on fluoroquinolones, were found in human clinical isolates on a plasmid in Escherichia coli and on the chromosome of Klebsiella pneumoniae. IS26-like sequences flanked the plasmid-mediated oqxAB genes, suggesting that they had been mobilized as part of a composite transposon.

Contribution of β-lactamase and efflux pump overproduction to tazobactam-piperacillin resistance in clinical isolates of Escherichia coli

2020 ◽  
Vol 55 (4) ◽  
pp. 105919 ◽  
Author(s):  
Yuuki Suzuki ◽  
Toyotaka Sato ◽  
Yukari Fukushima ◽  
Chie Nakajima ◽  
Yasuhiko Suzuki ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Efflux Pump ◽  
Clinical Isolates

scholarly journals Resistance/fitness trade-off is a barrier to the evolution of MarR inactivation mutants in Escherichia coli

2020 ◽  
Vol 76 (1) ◽  
pp. 77-83 ◽  
Author(s):  
Lisa Praski Alzrigat ◽  
Douglas L Huseby ◽  
Gerrit Brandis ◽  
Diarmaid Hughes
Keyword(s):  
Escherichia Coli ◽  
Experimental Evolution ◽  
Efflux Pump ◽  
Drug Susceptibility ◽  
Fitness Cost ◽  
Competitive Growth ◽  
Contributing Factors ◽  
Trade Off ◽  
Compensatory Evolution ◽  
The Cost

Abstract Background Mutations that inactivate MarR reduce susceptibility to ciprofloxacin and competitive growth fitness in Escherichia coli. Both phenotypes are caused by overexpression of the MarA regulon, which includes the AcrAB-TolC drug efflux pump. Objectives We asked whether compensatory evolution could reduce the fitness cost of MarR-inactivating mutations without affecting resistance to ciprofloxacin. Methods The cost of overexpressing the AcrAB-TolC efflux pump was measured independently of MarA overexpression. Experimental evolution of MarR-inactive strains was used to select mutants with increased fitness. The acquired mutations were identified and their effects on drug susceptibility were measured. Results Overexpression of the AcrAB-TolC efflux pump was found not to contribute to the fitness cost of MarA regulon overexpression. Fitness-compensatory mutations were selected in marA and lon. The mutations reduced the level of MarA protein thus reducing expression of the MarA regulon. They restored growth fitness but also reduced resistance to ciprofloxacin. Conclusions The fitness cost caused by overexpression of the MarA regulon has multiple contributing factors. Experimental evolution did not identify any single pump-independent cost factor. Instead, efficient fitness compensation occurred only by mechanisms that reduce MarA concentration, which simultaneously reduce the drug resistance phenotype. This resistance/fitness trade-off is a barrier to the successful spread of MarR inactivation mutations in clinical isolates where growth fitness is essential.

scholarly journals Mutations in efflux pump Rv1258c (Tap) cause resistance to pyrazinamide and other drugs inM. tuberculosis

2018 ◽  
Author(s):  
Jiayun Liu ◽  
Wanliang Shi ◽  
Shuo Zhang ◽  
Gail Cassell ◽  
Dmitry A. Maslov ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Drug Exposure ◽  
Efflux Pump ◽  
Active Form ◽  
Point Mutations ◽  
Drug Susceptibility ◽  
Clinical Isolates

AbstractAlthough drug resistance inM. tuberculosisis mainly caused by mutations in drug activating enzymes or drug targets, there is increasing interest in possible role of efflux in causing drug resistance. Previously, efflux genes are shown upregulated upon drug exposure or implicated in drug resistance in overexpression studies, but the role of mutations in efflux pumps identified in clinical isolates in causing drug resistance is unknown. Here we investigated the role of mutations in efflux pump Rv1258c (Tap) from clinical isolates in causing drug resistance inM. tuberculosisby constructing point mutations V219A, S292L in Rv1258c in the chromosome ofM. tuberculosisand assessed drug susceptibility of the constructed mutants. Interestingly, V219A, S292L point mutations caused clinically relevant drug resistance to pyrazinamide (PZA), isoniazid (INH), and streptomycin (SM), but not to other drugs inM. tuberculosis. While V219A point mutation conferred a low level resistance, the S292L mutation caused a higher level of resistance. Efflux inhibitor piperine inhibited INH and PZA resistance in the S292L mutant but not in the V219A mutant. S292L mutant had higher efflux activity for pyrazinoic acid (the active form of PZA) than the parent strain. We conclude that point mutations in the efflux pump Rv1258c in clinical isolates can confer clinically relevant drug resistance including PZA and could explain some previously unaccounted drug resistance in clinical strains. Future studies need to take efflux mutations into consideration for improved detection of drug resistance inM. tuberculosisand address their role in affecting treatment outcome in vivo.

scholarly journals Effect of azithromycin and phenylalanine-arginine beta-naphthylamide on quorum sensing and virulence factors in clinical isolates of Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Amel Elsheredy ◽  
Ingy El-Soudany ◽  
Eglal Elsherbini ◽  
Dalia Metwally ◽  
Abeer Ghazal
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Efflux Pump ◽  
Cell Communication ◽  
Inhibitory Effect ◽  
Resistance Rate ◽  
Clinical Isolates ◽  
Efflux Pump Inhibitor ◽  
Bacteria Growth

Background and Objectives: Pseudomonas aeruginosa is a problematic opportunistic pathogen causing several types of nosocomial infections with a high resistance rate to antibiotics. Production of many virulence factors in P. aeruginosa is regulated by quorum sensing (QS), a cell-to-cell communication mechanism. In this study, we aimed to assess and compare the inhibitory effect of azithromycin (AZM) and EPI- PAβN (efflux pump inhibitor- Phenylalanine-Arginine Beta-Naphthylamide) on QS system and QS-dependent virulence factors in P. aeruginosa clinical isolates. Materials and Methods: A total of 50 P. aeruginosa isolates were obtained from different types of clinical specimens. Isolates were investigated for detection of QS system molecules by AHL cross-feeding bioassay and QS-dependent virulence factors; this was also confirmed by detection of QS genes (lasR, lasI, rhlR, and rhlI) using PCR assay. The inhibitory effect of sub-MIC AZM and EPI PAβN on these virulence factors was assessed. Results: All the P. aeruginosa, producing QS signals C4 HSL, failed to produce C4 HSL in the presence of sub-MIC AZM, In the presence of EPI PAβN (20 µg/ml) only 14 isolates were affected, there was a significant reduction in QS-dependent virulence factors production (protease, biofilm, rhamnolipid and pyocyanin) in the presence of either 20 µg/ml EPI or subMIC of AZM with the inhibitory effect of AZM was more observed than PAβN. Conclusion: Anti-QS agents like AZM and EPI (PAβN) are useful therapeutic options for P. aeruginosa due to its inhibitory effect on QS-dependent virulence factors production without selective pressure on bacteria growth, so resistance to these agents is less likely to develop.

scholarly journals 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

2016 ◽  
Vol 60 (4) ◽  
pp. 1974-1983 ◽  
Author(s):  
Jürgen A. Bohnert ◽  
Sabine Schuster ◽  
Winfried V. Kern ◽  
Tadeusz Karcz ◽  
Agnieszka Olejarz ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Outer Membrane ◽  
Real Time ◽  
Near Infrared ◽  
Efflux Pump ◽  
Nile Red ◽  
Additional Mechanism ◽  
Efflux Pump Inhibitor ◽  
Content Type ◽  
Membrane Probes

ABSTRACTIn 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-overproducingEscherichia colistrain 3-AG100, whereas BM-9, BM-27, and BM-36 had no activity at concentrations of up to 50 μM in a Nile red efflux assay. MIC microdilution assays demonstrated that BM-19 at 1/4 MIC (intrinsic MIC, 200 μM) was able to reduce the MICs of levofloxacin, oxacillin, linezolid, and clarithromycin 8-fold. BM-38 at 1/4 MIC (intrinsic MIC, 100 μM) 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.

scholarly journals Mechanisms of Fluoroquinolone Resistance in Escherichia coli Isolates from Food-Producing Animals

2011 ◽  
Vol 77 (20) ◽  
pp. 7113-7120 ◽  
Author(s):  
Maria Karczmarczyk ◽  
Marta Martins ◽  
Teresa Quinn ◽  
Nola Leonard ◽  
Séamus Fanning
Keyword(s):  
Escherichia Coli ◽  
Nalidixic Acid ◽  
Target Genes ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Fluoroquinolone Resistance ◽  
Efflux Pump Inhibitor ◽  
Content Type ◽  
Field Isolates ◽  
K 12

ABSTRACTEleven multidrug-resistantEscherichia coliisolates (comprising 6 porcine and 5 bovine field isolates) displaying fluoroquinolone (FQ) resistance were selected from a collection obtained from the University Veterinary Hospital (Dublin, Ireland). MICs of nalidixic acid and ciprofloxacin were determined by Etest. All showed MICs of nalidixic acid of >256 μg/ml and MICs of ciprofloxacin ranging from 4 to >32 μg/ml. DNA sequencing was used to identify mutations within the quinolone resistance-determining regions of target genes, and quantitative real-time PCR (qRT-PCR) was used to evaluate the expression of the major porin, OmpF, and component genes of the AcrAB-TolC efflux pump and its associated regulatory loci. Decreased MIC values to nalidixic acid and/or ciprofloxacin were observed in the presence of the efflux pump inhibitor phenylalanine-arginine-β-naphthylamide (PAβN) in some but not all isolates. Several mutations were identified in genes coding for quinolone target enzymes (3 to 5 mutations per strain). All isolates harbored GyrA amino acid substitutions at positions 83 and 87. Novel GyrA (Asp87 → Ala), ParC (Ser80 → Trp), and ParE (Glu460 → Val) substitutions were observed. The efflux activity of these isolates was evaluated using a semiautomated ethidium bromide (EB) uptake assay. Compared to wild-typeE. coliK-12 AG100, isolates accumulated less EB, and in the presence of PAβN the accumulation of EB increased. Upregulation of theacrBgene, encoding the pump component of the AcrAB-TolC efflux pump, was observed in 5 of 11 isolates, while 10 isolates showed decreased expression of OmpF. This study identified multiple mechanisms that likely contribute to resistance to quinolone-based drugs in the field isolates studied.

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