The Importance of Efflux Systems in Antibiotic Resistance and Efflux Pump Inhibitors in the Management of Resistance

Aygül, Abdurrahman

doi:10.5578/mb.8964

Cited by 23 publications

(11 citation statements)

References 37 publications

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“…Efflux pump inhibitors have also been studied as potential adjuvants (Aygul 2015 ). Various molecules have been shown to inhibit efflux pumps including chlorpromazine, CCCP and reserpine (Aygul 2015 ; Sharma et al 2019 ).…”

Section: Elevation Of Aminoglycoside Uptake and Bactericidal Activity...mentioning

confidence: 99%

A mini-review: environmental and metabolic factors affecting aminoglycoside efficacy

Webster

Shepherd

2022

World J Microbiol Biotechnol

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Following the discovery of streptomycin from Streptomyces griseus in the 1940s by Selman Waksman and colleagues, aminoglycosides were first used to treat tuberculosis and then numerous derivatives have since been used to combat a wide variety of bacterial infections. These bactericidal antibiotics were used as first-line treatments for several decades but were largely replaced by ß-lactams and fluoroquinolones in the 1980s, although widespread emergence of antibiotic-resistance has led to renewed interest in aminoglycosides. The primary site of action for aminoglycosides is the 30 S ribosomal subunit where they disrupt protein translation, which contributes to widespread cellular damage through a number of secondary effects including rapid uptake of aminoglycosides via elevated proton-motive force (PMF), membrane damage and breakdown, oxidative stress, and hyperpolarisation of the membrane. Several factors associated with aminoglycoside entry have been shown to impact upon bacterial killing, and more recent work has revealed a complex relationship between metabolic states and the efficacy of different aminoglycosides. Hence, it is imperative to consider the environmental conditions and bacterial physiology and how this can impact upon aminoglycoside entry and potency. This mini-review seeks to discuss recent advances in this area and how this might affect the future use of aminoglycosides.

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Section: Elevation Of Aminoglycoside Uptake and Bactericidal Activity...mentioning

confidence: 99%

A mini-review: environmental and metabolic factors affecting aminoglycoside efficacy

Webster

Shepherd

2022

World J Microbiol Biotechnol

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“…Presently, many ABCB1 inhibitors have been found, such as calcium channel blockers (verapamil) [7,8], immunosuppressants (cyclosporine A) [9,10], and antihypertensive drugs (reserpine) [11,12]. However, some of the inhibitors are the substrate of ABCB1, and the inhibition of ABCB1 requires a high serum concentration of drugs, which may be toxic, and limits the application of these inhibitors [13][14][15]. Thus, in order to overcome MDR efficiently, it is essential to identify whether the inhibitor functions as a substrate.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

Wang

Yang

et al. 2020

IJMS

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The overexpressing ABCB1 transporter is one of the key factors leading to multidrug resistance (MDR). Thus, many ABCB1 inhibitors have been found to be able to overcome ABCB1-mediated MDR. However, some inhibitors also work as a substrate of ABCB1, which indicates that in order to achieve an effective reversal dosage, a higher concentration is needed to overcome the pumped function of ABCB1, which may concurrently increase the toxicity. WYE-354 is an effective and specific mTOR (mammalian target of rapamycin) inhibitor, which recently has been reported to reverse ABCB1-mediated MDR. In the current study, 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay was carried out to determine the cell viability and reversal effect of WYE-354 in parental and drug-resistant cells. Drug accumulation was performed to examine the effect of WYE-354 on the cellular accumulation of chemotherapeutic drugs. The ATPase (adenosine triphosphatase) activity of the ABCB1 transporter in the presence or absence of WYE-354 was conducted in order to determine the impact of WYE-354 on ATP hydrolysis. Western blot analysis and immunofluorescence assay were used to investigate the protein molecules related to MDR. In addition, the interaction between the WYE-354 and ABCB1 transporter was investigated via in silico analysis. We demonstrated that WYE-354 is a substrate of ABCB1, that the overexpression of the ABCB1 transporter decreases the efficacy of WYE-354, and that the resistant WYE-354 can be reversed by an ABCB1 inhibitor at a pharmacological achievable concentration. Furthermore, WYE-354 increased the intracellular accumulation of paclitaxel in the ABCB1-mediated MDR cell line, without affecting the corresponding parental cell line, which indicated that WYE-354 could compete with other chemotherapeutic drugs for the ABCB1 transporter substrate binding site. In addition, WYE-354 received a high score in the docking analysis, indicating a strong interaction between WYE-354 and the ABCB1 transporter. The results of the ATPase analysis showed that WYE-354 could stimulate ABCB1 ATPase activity. Treatment with WYE-354 did not affect the protein expression or subcellular localization of the ABCB1. This study provides evidence that WYE-354 is a substrate of the ABCB1 transporter, implicating that WYE-354 should be avoided for use in ABCB1-mediated MDR cancer.

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“…a transporter facilitating drug resistance by drug export. Furthermore, the inhibition of such efflux transporters has been suggested as an approach to counteract pathogenic resistant bacteria (33)(34)(35)(36)(37). Our study suggests that perhaps uptake transporters present in bacteria could be targeted with new derivatives of already known antibiotics, designed to have optimal influx.…”

Section: Ydgr Facilitates Chloramphenicol Uptakementioning

confidence: 84%

The prototypical proton-coupled oligopeptide transporter YdgR from Escherichia coli facilitates chloramphenicol uptake into bacterial cells

Prabhala

Aduri

Sharma

et al. 2018

Journal of Biological Chemistry

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Chloramphenicol (Cam) is a broad-spectrum antibiotic used to combat bacterial infections in humans and animals. Cam export from bacterial cells is one of the mechanisms by which pathogens resist Cam's antibacterial effects, and several different proteins are known to facilitate this process. However, to date no report exists on any specific transport protein that facilitates Cam uptake. The proton-coupled oligopeptide transporter (POT) YdgR from is a prototypical member of the POT family, functioning in proton-coupled uptake of di- and tripeptides. By following bacterial growth and conducting LC-MS-based assays we show here that YdgR facilitates Cam uptake. Some YdgR variants displaying reduced peptide uptake also exhibited reduced Cam uptake, indicating that peptides and Cam bind YdgR at similar regions. Homology modeling of YdgR, Cam docking, and mutational studies suggested a binding mode that resembles that of Cam binding to the multidrug resistance transporter MdfA. To our knowledge, this is the first report of Cam uptake into bacterial cells mediated by a specific transporter protein. Our findings suggest a specific bacterial transporter for drug uptake that might be targeted to promote greater antibiotic influx to increase cytoplasmic antibiotic concentration for enhanced cytotoxicity.

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The Importance of Efflux Systems in Antibiotic Resistance and Efflux Pump Inhibitors in the Management of Resistance

Cited by 23 publications

References 37 publications

A mini-review: environmental and metabolic factors affecting aminoglycoside efficacy

A mini-review: environmental and metabolic factors affecting aminoglycoside efficacy

Overexpression of ABCB1 Transporter Confers Resistance to mTOR Inhibitor WYE-354 in Cancer Cells

The prototypical proton-coupled oligopeptide transporter YdgR from Escherichia coli facilitates chloramphenicol uptake into bacterial cells

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