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The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance

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A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Mechanism and Evolution of Antibiotic Resistance".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 37918

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Special Issue Editor

Dr. Spengler Gabriella

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Department of Medical Microbiology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, 6725 Szeged, Hungary
Interests: reversal of multidrug resistance in bacteria; experimental chemotherapy
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Dear Colleagues,

Efflux pumps are protein constituents of all bacterial plasma membranes, and can recognize and extrude toxic compounds to the environment. The over-expression of these pumps is one of the hallmarks of the frequent failure of antimicrobial chemotherapy. For this reason the inhibition of efflux pumps could be an effective strategy to overcome multidrug resistance. Efflux pump inhibitors (EPIs) alone or in combination could restore the sensitivity of resistant strains by increasing the intracellular concentration of antibiotics and decreasing the level of intrinsic resistance. Concerning the chemical nature of EPIs, there are compounds from natural (plant) sources, semi-synthetic derivatives of existing EPIs, and fully synthetic EPIs as well.

This Special Issue of Antibiotics invites both reviews and original articles that consider efflux pump inhibitors as challenging tools to overcome multidrug resistance in bacteria.

Dr. Gabriella Spengler
Guest Editor

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Keywords

multidrug resistance
multidrug efflux pump
efflux pump inhibitor (EPI)
accumulation assay
efflux assay
fluorochromes
ethidium bromide
quorum sensing
biofilm

Published Papers (10 papers)

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10 pages, 574 KiB

Open AccessArticle

The Relationship between Antibiotic Susceptibility and pH in the Case of Uropathogenic Bacteria

by Annamária Kincses, Bálint Rácz, Zain Baaity, Orsolya Vásárhelyi, Erzsébet Kristóf, Ferenc Somogyvári and Gabriella Spengler

Antibiotics 2021, 10(12), 1431; https://doi.org/10.3390/antibiotics10121431 - 23 Nov 2021

Cited by 5 | Viewed by 3651

Abstract

Urinary tract infections (UTIs) are common bacterial infections caused mainly by enteric bacteria. Numerous virulence factors assist bacteria in the colonization of the bladder. Bacterial efflux pumps also contribute to bacterial communication and to biofilm formation. In this study, the phenotypic and genetic antibiotic resistance of clinical UTI pathogens such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis were determined by disk diffusion method and polymerase chain reaction (PCR). Following this, different classes of antibiotics were evaluated for their antibacterial activity at pH 5, 6, 7 and 8 by a microdilution method. Gentamicin (GEN) was the most potent antibacterial agent against E. coli strains. The effect of GEN on the relative expression of marR and sdiA genes was evaluated by quantitative PCR. The slightly acidic pH (pH 6) and GEN treatment induced the upregulation of marR antibiotic resistance and sdiA QS activator genes in both E. coli strains. Consequently, bacteria had become more susceptible to GEN. It can be concluded that antibiotic activity is pH dependent and so the artificial manipulation of urinary pH can contribute to a more effective therapy of multidrug resistant bacterial infections. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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13 pages, 2703 KiB

Open AccessArticle

Identified Seaweed Compound Diphenylmethane Serves as an Efflux Pump Inhibitor in Drug-Resistant Escherichia coli

by Wen-Jung Lu, Pang-Hung Hsu, Chun-Ju Chang, Cheng-Kuan Su, Yan-Jyun Huang, Hsuan-Ju Lin, Margaret Lai, Gui-Xia Ooi, Jing-Yi Dai and Hong-Ting Victor Lin

Antibiotics 2021, 10(11), 1378; https://doi.org/10.3390/antibiotics10111378 - 10 Nov 2021

Cited by 4 | Viewed by 2086

Abstract

Drug efflux pumps are one of the major elements used by antibiotic-resistant bacteria. Efflux pump inhibitors (EPIs) are potential therapeutic agents for adjunctive therapy, which can restore the activity of antibiotics that are no longer effective against pathogens. This study evaluated the seaweed compound diphenylmethane (DPM) for its EPI activity. The IC₅₀ and modulation results showed that DPM has no antibacterial activity but can potentiate the activity of antibiotics against drug-resistant E. coli. Time-kill studies reported that a combination of DPM and erythromycin exhibited greater inhibitory activity against drug-resistant Escherichia coli. Dye accumulation and dye efflux studies using Hoechst 33342 and ethidium bromide showed that the addition of DPM significantly increased dye accumulation and reduced dye efflux in drug-resistant E. coli, suggesting its interference with dye translocation by an efflux pump. Using MALDI-TOF, it was observed that the addition of DPM could continuously reduce antibiotic efflux in drug-resistant E. coli. Additionally, DPM did not seem to damage the E. coli membranes, and the cell toxicity test showed that it features mild human-cell toxicity. In conclusion, these findings showed that DPM could serve as a potential EPI for drug-resistant E. coli. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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18 pages, 2126 KiB

Open AccessArticle

Efflux Pump Inhibition and Resistance Modulation in Mycobacterium smegmatis by Peucedanum ostruthium and Its Coumarins

by Katarina Šimunović, Julia Solnier, Fabian Alperth, Olaf Kunert, Sonja Smole Možina and Franz Bucar

Antibiotics 2021, 10(9), 1075; https://doi.org/10.3390/antibiotics10091075 - 5 Sep 2021

Cited by 7 | Viewed by 2711

Abstract

Antibiotic resistance is a growing problem and may become the next major global health crisis if no timely actions are taken. Mycobacterial infections are widespread and, due to antibiotic resistance, also hard to treat and a major cause of mortality. Natural compounds have the potential to increase antibiotic effectiveness due to their resistance modulatory and antimicrobial effects. In this study, Peucedanum ostruthium extracts, fractions, and isolated compounds were investigated regarding their antimicrobial and resistance-modulatory effects as well as efflux pump inhibition in Mycobacterium smegmatis. P. ostruthium extracts were found to have anti-mycobacterial potential and resistance modulating effects on ethidium bromide activity. The major antibacterial effect was attributed to ostruthin, and we found that the more lipophilic the substrate, the greater the antimicrobial effect. Imperatorin caused potent modulatory effects by interfering with the action of the major LfrA efflux pump in M. smegmatis. The plant P. ostruthuim has a complex effect on M. smegmatis, including antibacterial, efflux pump inhibition, resistance modulation, and membrane permeabilization, and its major constituents, ostruthin and imperatorin, have a distinct role in these effects. This makes P. ostruthium and its coumarins promising therapeutics to consider in the fight against drug-resistant mycobacteria. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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13 pages, 1559 KiB

Open AccessArticle

Overexpression of the adeB Efflux Pump Gene in Tigecycline-Resistant Acinetobacter baumannii Clinical Isolates and Its Inhibition by (+)Usnic Acid as an Adjuvant

by Nagaraju Bankan, Fathimunnisa Koka, Rajagopalan Vijayaraghavan, Sreekanth Reddy Basireddy and Selvaraj Jayaraman

Antibiotics 2021, 10(9), 1037; https://doi.org/10.3390/antibiotics10091037 - 25 Aug 2021

Cited by 6 | Viewed by 2877

Abstract

Acinetobacter species are among the most life-threatening Gram-negative bacilli, causing hospital-acquired infections, and they are associated with high morbidity and mortality. They show multidrug resistance that acts via various mechanisms. In Acinetobacter baumannii, efflux pump-mediated resistance to many antimicrobial compounds, including tigecycline, has been widely reported. Natural compounds have been used for their various pharmacological properties, including anti-efflux pump activity. The present study aimed to evaluate the efflux pump-mediated resistance mechanism of Acinetobacter baumannii and the effect of (+)Usnic acid as an efflux pump inhibitor with tigecycline. For detecting the efflux pump activity of tigecycline-resistant Acinetobacter baumannii isolates, microbroth dilution method and real-time quantitative reverse transcription–polymerase chain reaction was used. (+)Usnic acid was added to tigecycline and tested by the checkerboard method to evaluate its efficacy as an efflux pump inhibitor. qRT-PCR analysis was carried out to show the downregulation of the efflux pump in the isolates. Out of 42 tigecycline-resistant Acinetobacter baumannii isolates, 19 showed efflux pump activity. All 19 strains expressed the adeB gene. (+)Usnic acid as an adjuvant showed better efficacy in lowering the minimum inhibitory concentration compared with the conventional efflux pump inhibitor, carbonyl cyanide phenylhydrazone. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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17 pages, 2364 KiB

Open AccessArticle

Xanthones Active against Multidrug Resistance and Virulence Mechanisms of Bacteria

by Fernando Durães, Diana I. S. P. Resende, Andreia Palmeira, Nikoletta Szemerédi, Madalena M. M. Pinto, Gabriella Spengler and Emília Sousa

Antibiotics 2021, 10(5), 600; https://doi.org/10.3390/antibiotics10050600 - 19 May 2021

Cited by 24 | Viewed by 4122

Abstract

The emergence of multidrug and extensively drug-resistant pathogenic bacteria able to resist to the action of a wide range of antibiotics is becoming a growing problem for public health. The search for new compounds with the potential to help in the reversion of bacterial resistance plays an important role in current medicinal chemistry research. Under this scope, bacterial efflux pumps are responsible for the efflux of antimicrobials, and their inhibition could reverse resistance. In this study, the multidrug resistance reversing activity of a series of xanthones was investigated. Firstly, docking studies were performed in the AcrAB-TolC efflux pump and in a homology model of the NorA pump. Then, the effects of twenty xanthone derivatives on bacterial growth were evaluated in Staphylococcus aureus 272123 and in the acrA gene-inactivated mutant Salmonella enterica serovar Typhimurium SL1344 (SE03). Their efflux pump inhibitory properties were assessed using real-time fluorimetry. Assays concerning the activity of these compounds towards the inhibition of biofilm formation and quorum sensing have also been performed. Results showed that a halogenated phenylmethanamine xanthone derivative displayed an interesting profile, as far as efflux pump inhibition and biofilm formation were concerned. To the best of our knowledge, this is the first report of xanthones as potential efflux pump inhibitors. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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17 pages, 1722 KiB

Open AccessArticle

Ketone- and Cyano-Selenoesters to Overcome Efflux Pump, Quorum-Sensing, and Biofilm-Mediated Resistance

by Nikoletta Szemerédi, Annamária Kincses, Katerina Rehorova, Lan Hoang, Noemi Salardón-Jiménez, Clotilde Sevilla-Hernández, Jitka Viktorová, Enrique Domínguez-Álvarez and Gabriella Spengler

Antibiotics 2020, 9(12), 896; https://doi.org/10.3390/antibiotics9120896 - 11 Dec 2020

Cited by 19 | Viewed by 3190

Abstract

The emergence of drug-resistant pathogens leads to a gradual decline in the efficacy of many antibacterial agents, which poses a serious problem for proper therapy. Multidrug resistance (MDR) mechanisms allow resistant bacteria to have limited uptake of drugs, modification of their target molecules, drug inactivation, or release of the drug into the extracellular space by efflux pumps (EPs). In previous studies, selenoesters have proved to be promising derivatives with a noteworthy antimicrobial activity. On the basis of these results, two series of novel selenoesters were synthesized to achieve more potent antibacterial activity on Gram-positive and Gram-negative bacteria. Fifteen selenoesters (eight ketone-selenoesters and seven cyano-selenoesters) were investigated with regards to their efflux pump-inhibiting, anti-quorum-sensing (QS), and anti-biofilm effects in vitro. According to the results of the antibacterial activity, the ketone-selenoesters proved to be more potent antibacterial compounds than the cyano-selenoesters. With regard to efflux pump inhibition, one cyano-selenoester on methicillin-resistant S. aureus and one ketone-selenoester on Salmonella Typhimurium were potent inhibitors. The biofilm inhibitory capacity and the ability of the derivatives to disrupt mature biofilms were noteworthy in all the experimental systems applied. Regarding QS inhibition, four ketone-selenoesters and three cyano-selenoesters exerted a noteworthy effect on Vibrio campbellii strains. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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12 pages, 596 KiB

Open AccessArticle

Benzoxazole-Based Metal Complexes to Reverse Multidrug Resistance in Bacteria

by Annamária Kincses, Stefánia Szabó, Bálint Rácz, Nikoletta Szemerédi, Genki Watanabe, Ryosuke Saijo, Hiroshi Sekiya, Eiji Tamai, Joseph Molnár, Masami Kawase and Gabriella Spengler

Antibiotics 2020, 9(10), 649; https://doi.org/10.3390/antibiotics9100649 - 28 Sep 2020

Cited by 12 | Viewed by 2929

Abstract

Bacteria often show resistance against antibiotics due to various mechanisms such as the expression of efflux pumps, biofilm formation, or bacterial quorum sensing (QS) controls. For successful therapy, the discovery of alternative agents is crucial. The objective of this study was to evaluate the efflux pump, anti-biofilm, and QS inhibiting, as well as antibacterial effects of 2-trifluoroacetonylbenzoxazole ligands (1–3) and their metal complexes (4–12) in bacteria. The ligand 2 and its Zn(II) complex 5, and furthermore the Cu(II) complex 7 of ligand 1, exerted remarkable antibacterial activity on the Staphylococcus aureus 272123 (MRSA) strain. In the minimum inhibitory concentration (MIC) reduction assay the ligand 3, the Zn(II) complex 5 of ligand 2, and the Cu(II), Ni(II), Mg(II), Fe(III) complexes (7, 8, 9, 12) of ligand 1 enhanced the antibacterial activity of ciprofloxacin in MRSA. An increased ethidium bromide accumulation was detected for ligand 3 in MRSA while the Fe(III) complex 12 of ligand 1 decreased the biofilm formation of the reference S. aureus ATCC 25923 strain. The Zn(II) and Ag(II) complexes (3 and 4) of ligand 1 and ligand 3 inhibited the QS. Based on our results, the ligands and their metal complexes could be potential alternative drugs in the treatment of infectious diseases. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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20 pages, 4080 KiB

Open AccessArticle

Determination of Drug Efflux Pump Efficiency in Drug-Resistant Bacteria Using MALDI-TOF MS

by Wen-Jung Lu, Hsuan-Ju Lin, Pang-Hung Hsu and Hong-Ting Victor Lin

Antibiotics 2020, 9(10), 639; https://doi.org/10.3390/antibiotics9100639 - 24 Sep 2020

Cited by 10 | Viewed by 4409

Abstract

Multidrug efflux pumps play an essential role in antibiotic resistance. The conventional methods, including minimum inhibitory concentration and fluorescent assays, to monitor transporter efflux activity might have some drawbacks, such as indirect evidence or interference from color molecules. In this study, MALDI-TOF MS use was explored for monitoring drug efflux by a multidrug transporter, and the results were compared for validation with the data from conventional methods. Minimum inhibitory concentration was used first to evaluate the activity of Escherichia coli drug transporter AcrB, and this analysis showed that the E. coli overexpressing AcrB exhibited elevated resistance to various antibiotics and dyes. Fluorescence-based studies indicated that AcrB in E. coli could decrease the accumulation of intracellular dyes and display various efflux rate constants for different dyes, suggesting AcrB’s efflux activity. The MALDI-TOF MS analysis parameters were optimized to maintain a detection accuracy for AcrB’s substrates; furthermore, the MS data showed that E. coli overexpressing AcrB led to increased ions abundancy of various dyes and drugs in the extracellular space at different rates over time, illustrating continuous substrate efflux by AcrB. This study concluded that MALDI-TOF MS is a reliable method that can rapidly determine the drug pump efflux activity for various substrates. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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12 pages, 1350 KiB

Open AccessArticle

Chalcones Isolated from Arrabidaea brachypoda Flowers as Inhibitors of NorA and MepA Multidrug Efflux Pumps of Staphylococcus aureus

by Luís Mário Rezende-Júnior, Leila Maria de Sousa Andrade, Antonio Linkoln Alves Borges Leal, Avilnete Belem de Souza Mesquita, Ana Lurdes Portela de Araújo dos Santos, José de Sousa Lima Neto, José Pinto Siqueira-Júnior, Carlos Emídio Sampaio Nogueira, Glenn William Kaatz, Henrique Douglas Melo Coutinho, Natália Martins, Cláudia Quintino da Rocha and Humberto Medeiros Barreto

Antibiotics 2020, 9(6), 351; https://doi.org/10.3390/antibiotics9060351 - 20 Jun 2020

Cited by 34 | Viewed by 4203

Abstract

Bacterial resistance to antibiotics has become a public health issue around the world. The present study aimed to evaluate the antibacterial activity of chalcones isolated from flowers of Arrabidaea brachypoda, and their potential as efflux pump inhibitors of Staphylococcus aureus efflux pumps. Microdilution assays were performed with natural products from A. brachypoda. Chalcones 1, 3, 4, and 5 did not show intrinsic antimicrobial activity against all S. aureus strains tested, but they were able to potentiate the Norfloxacin action against the SA1199-B (norA) strain, with a better modulating action for the 4 trimethoxylated chalcone. All chalcones were also able to potentiate the action of EtBr against SA1199-B strain, suggesting a potential NorA inhibition. Moreover, chalcone 4 was able to interfere in the activity of MepA, and interfered weakly in the QacA/B activity. Molecular docking analyzes showed that tested chalcones are capable of binding in the hydrophobic cavity of NorA and MepA, in the same Norfloxacin binding site, indicating that chalcone 4 compete with the antibiotic for the same NorA and MepA binding sites. Association of chalcone 4 with Norfloxacin could be an alternative against multidrug resistant S. aureus over-productive of NorA or MepA. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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7 pages, 754 KiB

Open AccessPerspective

The Role of Efflux Pumps in the Transition from Low-Level to Clinical Antibiotic Resistance

by Anna Elisabeth Ebbensgaard, Anders Løbner-Olesen and Jakob Frimodt-Møller

Antibiotics 2020, 9(12), 855; https://doi.org/10.3390/antibiotics9120855 - 30 Nov 2020

Cited by 26 | Viewed by 5511

Abstract

Antibiotic resistance is on the rise and has become one of the biggest public health challenges of our time. Bacteria are able to adapt to the selective pressure exerted by antibiotics in numerous ways, including the (over)expression of efflux pumps, which represents an ancient bacterial defense mechanism. Several studies show that overexpression of efflux pumps rarely provides clinical resistance but contributes to a low-level resistance, which allows the bacteria to persist at the infection site. Furthermore, recent studies show that efflux pumps, apart from pumping out toxic substances, are also linked to persister formation and increased spontaneous mutation rates, both of which could aid persistence at the infection site. Surviving at the infection site provides the low-level-resistant population an opportunity to evolve by acquiring secondary mutations in antibiotic target genes, resulting in clinical resistance to the treating antibiotic. Thus, this emphasizes the importance and challenge for clinicians to be able to monitor overexpression of efflux pumps before low-level resistance develops to clinical resistance. One possible treatment option could be an efflux pump-targeted approach using efflux pump inhibitors. Full article

(This article belongs to the Special Issue The Role of Efflux Pump Inhibitor in Bacterial Multidrug Resistance)

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