Efflux Pump Contribution to Multidrug Resistance in Pseudomonas Aeruginosa and the Effect of Using an Efflux Pump Inhibitor on Ciprofloxacin Resistance

2012 ◽  
Vol 21 (2) ◽  
pp. 91-104
Author(s):  
Enas E. El-Said ◽  
Salwa R. Ali ◽  
Doaa M. Zakaria
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistance ◽  
Efflux Pump ◽  
Efflux Pump Inhibitor ◽  
Ciprofloxacin Resistance

scholarly journals Efflux Pump-Driven Antibiotic and Biocide Cross-Resistance in Pseudomonas aeruginosa Isolated from Different Ecological Niches: A Case Study in the Development of Multidrug Resistance in Environmental Hotspots

2020 ◽  
Vol 8 (11) ◽  
pp. 1647 ◽  
Author(s):  
Anteneh Amsalu ◽  
Sylvia A. Sapula ◽  
Miguel De Barros Lopes ◽  
Bradley J. Hart ◽  
Anh H. Nguyen ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistance ◽  
Antimicrobial Resistance ◽  
Molecular Mechanisms ◽  
Efflux Pump ◽  
Principal Component ◽  
Cross Resistance ◽  
Clinical Samples ◽  
Ecological Niches ◽  
Efflux Pump Inhibitor

Pseudomonas aeruginosa is an opportunistic pathogen displaying high intrinsic antimicrobial resistance and the ability to thrive in different ecological environments. In this study, the ability of P. aeruginosa to develop simultaneous resistance to multiple antibiotics and disinfectants in different natural niches were investigated using strains collected from clinical samples, veterinary samples, and wastewater. The correlation between biocide and antimicrobial resistance was determined by employing principal component analysis. Molecular mechanisms linking biocide and antimicrobial resistance were interrogated by determining gene expression using RT-qPCR and identifying a potential genetic determinant for co- and cross-resistance using whole-genome sequencing. A subpopulation of P. aeruginosa isolates belonging to three sequence types was resistant against the common preservative benzalkonium chloride and showed cross-resistance to fluoroquinolones, cephalosporins, aminoglycosides, and multidrug resistance. Of these, the epidemiological high-risk ST235 clone was the most abundant. The overexpression of the MexAB-OprM drug efflux pump resulting from amino acid mutations in regulators MexR, NalC, or NalD was the major contributing factor for cross-resistance that could be reversed by an efflux pump inhibitor. This is the first comparison of antibiotic-biocide cross-resistance in samples isolated from different ecological niches and serves as a confirmation of laboratory-based studies on biocide adapted isolates. The isolates from wastewater had a higher incidence of multidrug resistance and biocide-antibiotic cross-resistance than those from clinical and veterinary settings.

scholarly journals Use of an Efflux Pump Inhibitor To Determine the Prevalence of Efflux Pump-Mediated Fluoroquinolone Resistance and Multidrug Resistance in Pseudomonas aeruginosa

2005 ◽  
Vol 49 (2) ◽  
pp. 565-570 ◽  
Author(s):  
Jane Kriengkauykiat ◽  
Edith Porter ◽  
Olga Lomovskaya ◽  
Annie Wong-Beringer
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistance ◽  
Substrate Specificity ◽  
Efflux Pump ◽  
Fluoroquinolone Resistance ◽  
Cross Resistance ◽  
Broth Microdilution ◽  
Efflux Pump Inhibitor ◽  
Broad Substrate Specificity ◽  
Resistant Strains

ABSTRACT Fluoroquinolone-resistance in Pseudomonas aeruginosa may be due to efflux pump overexpression (EPO) and/or target mutations. EPO can result in multidrug resistance (MDR) due to broad substrate specificity of the pumps. MC-04,124, an efflux pump inhibitor (EPI) shown to significantly potentiate activity of levofloxacin in P. aeruginosa, was used to examine the prevalence of EPO in clinical isolates. MICs were determined for ciprofloxacin, levofloxacin, moxifloxacin, and gatifloxacin with or without EPI and for other antipseudomonal agents by using broth microdilution against P. aeruginosa isolates from adults (n = 119) and children (n = 24). The prevalence of the EPO phenotype (≥8-fold MIC decrease when tested with EPI) was compared among subgroups with different resistance profiles. The EPO phenotype was more prevalent among levofloxacin-resistant than levofloxacin-sensitive strains (61%, 48/79 versus 9%, 6/64). EPO was present in 60% of fluoroquinolone-resistant strains without cross-resistance, while it was present at variable frequencies among strains with cross-resistance to other agents: piperacillin-tazobactam (86%), ceftazidime (76%), cefepime (65%), imipenem (56%), gentamicin (55%), tobramycin (48%), and amikacin (27%). The magnitude of MIC decrease with an EPI paralleled the frequency of which the EPO phenotype was observed in different subgroups. EPI reduced the levofloxacin MIC by as much as 16-fold in eight strains for which MICs were 128 μg/ml. Efflux-mediated resistance appears to contribute significantly to fluoroquinolone resistance and MDR in P. aeruginosa. Our data support the fact that increased fluoroquinolone usage can negatively impact susceptibility of P. aeruginosa to multiple classes of antipseudomonal agents.

scholarly journals The Impact of an Efflux Pump Inhibitor on the Activity of Free and Liposomal Antibiotics against Pseudomonas aeruginosa

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 577
Author(s):  
Douweh Leyla Gbian ◽  
Abdelwahab Omri
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Antimicrobial Activities ◽  
Dilution Method ◽  
Efflux Pump Inhibitor ◽  
Signal Production ◽  
Lung Infections ◽  
The Impact ◽  
Microbroth Dilution

The eradication of Pseudomonas aeruginosa in cystic fibrosis patients has become continuously difficult due to its increased resistance to treatments. This study assessed the efficacy of free and liposomal gentamicin and erythromycin, combined with Phenylalanine arginine beta-naphthylamide (PABN), a broad-spectrum efflux pump inhibitor, against P. aeruginosa isolates. Liposomes were prepared and characterized for their sizes and encapsulation efficiencies. The antimicrobial activities of formulations were determined by the microbroth dilution method. Their activity on P. aeruginosa biofilms was assessed, and the effect of sub-inhibitory concentrations on bacterial virulence factors, quorum sensing (QS) signals and bacterial motility was also evaluated. The average diameters of liposomes were 562.67 ± 33.74 nm for gentamicin and 3086.35 ± 553.95 nm for erythromycin, with encapsulation efficiencies of 13.89 ± 1.54% and 51.58 ± 2.84%, respectively. Liposomes and PABN combinations potentiated antibiotics by reducing minimum inhibitory and bactericidal concentrations by 4–32 fold overall. The formulations significantly inhibited biofilm formation and differentially attenuated virulence factor production as well as motility. Unexpectedly, QS signal production was not affected by treatments. Taken together, the results indicate that PABN shows potential as an adjuvant of liposomal macrolides and aminoglycosides in the management of lung infections in cystic fibrosis patients.

scholarly journals Target (MexB)- and Efflux-Based Mechanisms Decreasing the Effectiveness of the Efflux Pump Inhibitor D13-9001 in Pseudomonas aeruginosa PAO1: Uncovering a New Role for MexMN-OprM in Efflux of β-Lactams and a Novel Regulatory Circuit (MmnRS) Controlling MexMN Expression

2018 ◽  
Vol 63 (2) ◽  
pp. e01718-18 ◽  
Author(s):  
Srijan Ranjitkar ◽  
Adriana K. Jones ◽  
Mina Mostafavi ◽  
Zachary Zwirko ◽  
Oleg Iartchouk ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Response Regulator ◽  
Heavy Metal Resistance ◽  
Metal Resistance ◽  
Rna Seq ◽  
Efflux Pump Inhibitor ◽  
Content Type ◽  
Regulatory Circuit ◽  
Outer Membrane Channel

ABSTRACT Efflux pumps contribute to antibiotic resistance in Gram-negative pathogens. Correspondingly, efflux pump inhibitors (EPIs) may reverse this resistance. D13-9001 specifically inhibits MexAB-OprM in Pseudomonas aeruginosa. Mutants with decreased susceptibility to MexAB-OprM inhibition by D13-9001 were identified, and these fell into two categories: those with alterations in the target MexB (F628L and ΔV177) and those with an alteration in a putative sensor kinase of unknown function, PA1438 (L172P). The alterations in MexB were consistent with reported structural studies of the D13-9001 interaction with MexB. The PA1438L172P alteration mediated a >150-fold upregulation of MexMN pump gene expression and a >50-fold upregulation of PA1438 and the neighboring response regulator gene, PA1437. We propose that these be renamed mmnR and mmnS for MexMN regulator and MexMN sensor, respectively. MexMN was shown to partner with the outer membrane channel protein OprM and to pump several β-lactams, monobactams, and tazobactam. Upregulated MexMN functionally replaced MexAB-OprM to efflux these compounds but was insusceptible to inhibition by D13-9001. MmnSL172P also mediated a decrease in susceptibility to imipenem and biapenem that was independent of MexMN-OprM. Expression of oprD, encoding the uptake channel for these compounds, was downregulated, suggesting that this channel is also part of the MmnSR regulon. Transcriptome sequencing (RNA-seq) of cells encoding MmnSL172P revealed, among other things, an interrelationship between the regulation of mexMN and genes involved in heavy metal resistance.

scholarly journals Curcumin as Efflux Pump Inhibitor Agent for Enhancement Treatment Against Multidrug Resistant Pseudomonas aeruginosa Isolates

2020 ◽  
pp. 59-67
Author(s):  
Sulaiman D. Sulaiman ◽  
Ghusoon A. Abdulhasan
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Inhibitory Concentration ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Disc Diffusion Method ◽  
Efflux Pump Inhibitor ◽  
Before And After ◽  
Chromogenic Agar ◽  
Susceptibility Patterns

  Pseudomonas aeruginosa is considered as a developing opportunistic nosocomial pathogen and is well-known for its multidrug resistance that can be efficiently treated by a combination of antibiotics andefflux pump inhibitors (EPI). Therefore, the purpose of this study was to investigate the effect of curcumin as an EPI for the enhancement of the effectiveness of antibiotics against multidrug resistant (MDR) isolates ofP. aeruginosa. Susceptibility patterns of suspected bacteria was determined using the disc diffusion method andresistant bacteria were identified using chromogenic agar and 16S rDNA. The effectsof curcuminon the enhancement of antibiotics’s activity was evaluated usingthe broth microdilution method.The susceptibility patterns for 50 (67.6%) suspectedP. aeruginosaisolates showed that 36 (72%) of these isolateswere resistant to one of the used antibiotics,whereasonly 21 (42%) were MDR. The highest percentage of resistance was observedtoceftazidime (66%) followed by ciprofloxacin and levofloxacin (40%). Only 35 isolates were specified by chromogenic agar and 16S rDNAas P. aeruginosa.The minimal inhibitory concentration (MIC) of 35 isolates for ciprofloxacin resistant was between 4 and128 µg/ml while for ceftazidime was between 64and 512 µg/ml. After the addition of 50 μg/ml curcumin with ciprofloxacin, there wasa significant increase in the sensitivity (p≤ 0.01) of 13 MDR P.aeroginosa isolates whereas no differences in the sensitivity to ceftazidime were recorded before and after addition ofcurcumin. In conclusion, the results of this study show that curcumin can decrease the MIC value of ciprofloxacin in MDR isolates of P. aeruginosaand can be used as a native compound to enhance the treatment of resistant isolates with ciprofloxacin.

scholarly journals Investigation of Ciprofloxacin Resistance and Its Mechanisms in Clinical Pseudomonas aeruginosa Isolates

ANKEM Dergisi ◽  
2021 ◽  
Author(s):  
Nilüfer Uzunbayır Akel ◽  
Yamaç Tekintaş ◽  
Fethiye Ferda Yılmaz ◽  
İsmail Öztürk ◽  
Mustafa Ökeer ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Efflux Pump ◽  
Resistance Mechanisms ◽  
Regulatory Genes ◽  
Quinolone Resistance ◽  
University Hospital ◽  
Clinical Samples ◽  
Genetic Groups ◽  
Ciprofloxacin Resistance ◽  
Polymerase Chain

Pseudomonas aeruginosa is one of the most important causes of hospital infections. Although different antibiotic groups are used for the treatment of P.aeruginosa infections, quinolone groups are distinguished by the advantages of oral administration. However, in recent years, resistance against members of this group has made treatment more difficult. The aim of this study was to investigate the epidemiological relationship and possible mechanisms of resistance in ciprofloxacin resistant P. aeruginosa isolates from Ege University Hospital. The identification of P.aeruginosa bacteria isolated from clinical samples in Ege University Medical Faculty Medical Microbiology Laboratory was determined by VITEK MS automated systems by VITEK compact, antimicrobial susceptibility. The epidemiological relationships of the ciprofloxacin resistant isolates were determined by Enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR). The presence of qnrA, qnrB, qnrS, qepA genes, the quinolone resistance genes and nfxB, mexR, the regulatory genes of the efflux pump, was determined by PCR. The phenylalanine-arginine β-naphthylamide (PAβN) assay was used to determine the activation of the efflux pump. Twenty-two isolates (26.5 %) were found resistant to ciprofloxacin. According to the ERIC-PCR results, 11 unrelated clones were detected. Ciprofloxacin minimum inhibitory concentration (MIC) values were decreased 2-64 times in 10 isolates in the presence of PAIN. No ciprofloxacin MIC change was detected in one isolate. The presence of pump regulatory genes was determined in 10 of the 11 representative isolates, while only qnrB of the genes associated with quinolone resistance was detected in seven representative isolates. qnrA, qnrS, qepA genes were not detected in any isolate. Ciprofloxacin resistant P.aeruginosa isolates are isolated from our hospital. It is noteworthy that the isolates belonging to different genetic groups are in circulation in clinics. Basic resistance mechanisms are thought to be efflux pumps and qnrB genes.

scholarly journals Synergistic Activities of an Efflux Pump Inhibitor and Iron Chelators against Pseudomonas aeruginosa Growth and Biofilm Formation

2010 ◽  
Vol 54 (9) ◽  
pp. 3960-3963 ◽  
Author(s):  
Yang Liu ◽  
Liang Yang ◽  
Søren Molin
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Iron Chelators ◽  
Acetohydroxamic Acid ◽  
Efflux Pump Inhibitor

ABSTRACT The efflux pump inhibitor phenyl-arginine-β-naphthylamide (PAβN) was paired with iron chelators 2,2′-dipyridyl, acetohydroxamic acid, and EDTA to assess synergistic activities against Pseudomonas aeruginosa growth and biofilm formation. All of the tested iron chelators synergistically inhibited P. aeruginosa growth and biofilm formation with PAβN. PAβN-EDTA showed the most promising activity against P. aeruginosa growth and biofilm formation.

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