Cocktail of CuO, ZnO, or CuZn Nanoparticles and Antibiotics for Combating Multidrug-Resistant Pseudomonas aeruginosa via Efflux Pump Inhibition

ABSTRACT Multidrug-resistant Pseudomonas aeruginosa with combined decreased susceptibility to ceftazidime, ciprofloxacin, imipenem, and piperacillin is increasingly being found as a cause of nosocomial infections. It is important to look for combinations of drugs that might be synergistic. Ciprofloxacin resistance by P. aeruginosa is mediated in part by an efflux pump mechanism. Gatifloxacin, an 8-methoxyfluoroquinolone, inhibits a staphylococcal efflux pump. An earlier in vitro study using an Etest synergy method and time-kill assay suggested synergy of ciprofloxacin and gatifloxacin against P. aeruginosa. Synergy testing was performed by Etest and time-kill assay for 31 clinically unique, plasmid DNA distinct, U.S. P. aeruginosa isolates. Etest MICs for ciprofloxacin were 4 to >32 μg/ml, and for gatifloxacin they were >32 μg/ml. Ciprofloxacin plus gatifloxacin showed synergy by the Etest method for 6 (19%) of the 31 P. aeruginosa isolates using a summation fractional inhibitory concentration of ≤0.5 for synergy. Synergy was demonstrated for 13/31 (42%) of isolates by time-kill assay. No antagonism was detected. The remaining isolates were indifferent to the combination. The Etest method and time-kill assay were 65% (20/31) concordant. The mechanism of the in vitro synergy may include P. aeruginosa ciprofloxacin efflux pump inhibition by gatifloxacin.

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Role of Efflux Pump in Biofilm Formation of Multidrug-Resistant Pseudomonas aeruginosa

4th International Symposium on Innovative Approaches in Health and Sports Sciences Proceedings ◽

10.36287/setsci.4.9.081 ◽

2019 ◽

Author(s):

Ceren Başkan ◽

Belgin Sırıken

Keyword(s):

Pseudomonas Aeruginosa ◽

Biofilm Formation ◽

Efflux Pump ◽

Multidrug Resistant

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

Iraqi Journal of Science ◽

10.24996/ijs.2020.61.1.6 ◽

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.

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Molecular mechanisms of efflux pump mediated resistance in clinical isolates of multidrug resistant pseudomonas aeruginosa

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2016.02.269 ◽

2016 ◽

Vol 45 ◽

pp. 104 ◽

Cited By ~ 1

Author(s):

L. Mohanam ◽

L. Priya ◽

E.M. Selvam ◽

S.S. Shivekar ◽

T. Menon

Keyword(s):

Pseudomonas Aeruginosa ◽

Molecular Mechanisms ◽

Efflux Pump ◽

Multidrug Resistant ◽

Clinical Isolates

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Involvement of Fe Uptake Systems and AmpC β-Lactamase in Susceptibility to the Siderophore Monosulfactam BAL30072 in Pseudomonas aeruginosa

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02474-12 ◽

2013 ◽

Vol 57 (5) ◽

pp. 2095-2102 ◽

Cited By ~ 26

Author(s):

Christian van Delden ◽

Malcolm G. P. Page ◽

Thilo Köhler

Keyword(s):

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Receptor Gene ◽

Sufficient Conditions ◽

Multidrug Resistant ◽

Content Type ◽

Single Nucleotide Change ◽

Gene Coding ◽

Iron Deficient ◽

Iron Receptor

ABSTRACTBAL30072 is a monosulfactam conjugated with an iron-chelating dihydroxypyridone moiety. It is active against Gram-negative bacteria, including multidrug-resistantPseudomonas aeruginosa. We selected mutants with decreased susceptibilities to BAL30072 inP. aeruginosaPAO1 under a variety of conditions. Under iron-deficient conditions, mutants with overexpression of AmpC β-lactamase predominated. These mutants were cross-resistant to aztreonam and ceftazidime. Similar mutants were obtained after selection at >16× the MIC in iron-sufficient conditions. At 4× to 8× the MIC, mutants with elevated MIC for BAL30072 but unchanged MICs for aztreonam or ciprofloxacin were selected. The expression ofampCand the major efflux pump genes were also unchanged. These BAL30072-specific mutants were characterized by transcriptome analysis, which revealed upregulation of the Fe-dicitrate operon, FecIRA. Whole-genome sequencing showed that this resulted from a single nucleotide change in the Fur-box of thefecIpromoter. Overexpression of either the FecI ECF sigma factor or the FecA receptor increased BAL30072 MICs 8- to 16-fold. AfecImutant and afecAmutant of PAO1 were hypersusceptible to BAL30072 (MICs < 0.06 μg/ml). The most downregulated gene belonged to the pyochelin synthesis operon, although mutants in pyochelin receptor or synthesis genes had unchanged MICs. ThepiuCgene, coding for a Fe(II)-dependent dioxygenase located next to thepiuAiron receptor gene, was also downregulated. The MICs of BAL30072 forpiuCandpiuAtransposon mutants were increased 8- and 16-fold, respectively. We conclude that the upregulation of the Fe-dicitrate system impacts the expression of other TonB-dependent iron transporters and that PiuA and PiuC contribute to the susceptibility ofP. aeruginosaPAO1 to BAL30072.

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Tobramycin-Linked Efflux Pump Inhibitor Conjugates Synergize Fluoroquinolones, Rifampicin and Fosfomycin against Multidrug-Resistant Pseudomonas aeruginosa

Journal of Clinical Medicine ◽

10.3390/jcm7070158 ◽

2018 ◽

Vol 7 (7) ◽

pp. 158 ◽

Cited By ~ 10

Author(s):

Xuan Yang ◽

Ronald Domalaon ◽

Yinfeng Lyu ◽

George Zhanel ◽

Frank Schweizer

Keyword(s):

Pseudomonas Aeruginosa ◽

Efflux Pump ◽

Multidrug Resistant ◽

Efflux Pump Inhibitor

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Trp-Containing Antibacterial Peptides Impair Quorum Sensing and Biofilm Development in Multidrug-Resistant Pseudomonas aeruginosa and Exhibit Synergistic Effects With Antibiotics

Frontiers in Microbiology ◽

10.3389/fmicb.2021.611009 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dejing Shang ◽

Xue Han ◽

Wanying Du ◽

Zhiru Kou ◽

Fengquan Jiang

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibacterial Activity ◽

Quorum Sensing ◽

Virulence Factors ◽

Biofilm Formation ◽

Efflux Pump ◽

Synergistic Effects ◽

Multidrug Resistant ◽

Biofilm Development ◽

Antibiotic Efflux

Pseudomonas aeruginosa uses quorum sensing (QS) to control virulence, biofilm formation and antibiotic efflux pump expression. The development of effective small molecules targeting the QS system and biofilm formation represents a novel attractive strategy. In this present study, the effects of a series of Trp-containing peptides on the QS-regulated virulence and biofilm development of multidrug-resistant P. aeruginosa, as well as their synergistic antibacterial activity with three classes of traditional chemical antibiotics were investigated. The results showed that Trp-containing peptides at low concentrations reduced the production of QS-regulated virulence factors by downregulating the gene expression of both the las and rhl systems in the strain MRPA0108. Biofilm formation was inhibited in a concentration-dependent manner, which was associated with extracellular polysaccharide production inhibition by downregulating pelA, algD, and pslA transcription. These changes correlated with alterations in the extracellular production of pseudomonal virulence factors and swarming motility. In addition, the combination of Trp-containing peptides at low concentration with the antibiotics ceftazidime and piperacillin provided synergistic effects. Notably, L11W and L12W showed the highest synergy with ceftazidime and piperacillin. A mechanistic study demonstrated that the Trp-containing peptides, especially L12W, significantly decreased β-lactamase activity and expression of efflux pump genes OprM, MexX, and MexA, resulting in a reduction in antibiotic efflux from MRPA0108 cells and thus increasing the antibacterial activity of these antibiotics against MRPA0108.

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First Isolation and Characterization of Chryseobacterium cucumeris SKNUCL01, Isolated from Diseased Pond loach (Misgurnus anguillicaudatus) in Korea

Pathogens ◽

10.3390/pathogens9050397 ◽

2020 ◽

Vol 9 (5) ◽

pp. 397

Author(s):

Sang Guen Kim ◽

Sib Giri ◽

Sang Wha Kim ◽

Jun Kwon ◽

Sung Bin Lee ◽

...

Keyword(s):

Antibiotic Resistance ◽

Bacterial Infections ◽

Efflux Pump ◽

Lethal Dose ◽

Multidrug Resistant ◽

Misgurnus Anguillicaudatus ◽

Beta Lactamases ◽

Isolation And Characterization ◽

Efflux Pump Inhibition ◽

Synergy Test

Loaches are widely distributed throughout the natural environment and are consumed for medicinal purposes in East Asia. Usually, loaches are cultured in ponds where the water conditions can easily cause bacterial infections. Infections due to bacterial pathogens such as Aeromonas have been well described in cultured loaches; however, there is no report regarding Chryseobacterium infection. This study focused on the elucidation of the pathogenic and antibiotic resistance characteristics of C. cucumeris, SKNUCL01, isolated from diseased loaches (Misgurnus anguillicaudatus). SKNUCL01 forms a biofilm, which is associated with its virulence. Koch’s postulates were satisfied with a lethal dose 50 (LD50) of 8.52 × 107 colony-forming units (CFU)/ml. Abrasion facilitates the mortality of the fish, which makes it a possible infection route for C. cucumeris. The strain showed resistance to nearly all tested antibiotics, such as trimethoprim/sulfamethoxazole, levofloxacin, and ciprofloxacin, formerly considered effective treatments. Phenotypic analyses for antibiotic resistance—the combined disk test, double-disk synergy test, modified Hodge test, and efflux pump inhibition test—revealed that the resistance of SKNUCL01 originated from metallo-beta lactamases (MBLs) and efflux pumps. Our findings provide evidence that could result in a breakthrough against multidrug-resistant Chryseobacterium infection in the aquaculture industry; the antibiotic resistance-related genes can be elucidated through future study.

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