Red Blood Cell Na<sup>+</sup>, K<sup>+</sup> Pump Activity in Patients on Hemofiltration
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The intracellular concentration of Na+ ([Na+i]) and the Na+ efflux mediated by the Na+, K+ pump were evaluated in red blood cells from 9 patients on hemofiltration, 8 on hemodialysis, 9 on continuous ambulatory peritoneal dialysis (CAPD) and 12 normal subjects. [Na+i] was elevated in CAPD patients only. The rate constant for pump-mediated sodium efflux was close to normal in hemofiltration patients, and significantly reduced in hemodialysis (p < 0.03) and CAPD (p < 0.01) patients. Uremic plasma from subjects on hemodialysis and CAPD, but not from hemofiltration, significantly (p < 0.001) inhibited the Na+, K+ pump activity of normal red blood cells. Among our uremic patients those on hemofiltration showed a red blood cell Na+, K+ pump activity close to that of normal subjects, possibly related to the absence in their plasma of a circulating pump inhibitor, that seems invariably present in plasma from hemodialysis and CAPD patients.Keywords:
Hemofiltration
Efflux
Sodium pump
The increasing multi-drug resistance has become a major threat to the public health. Overexpression of multidrug efflux pumps is one of the major mechanisms of drug resistance in bacteria. Since active efflux of antibacterial agents plays a significant role in mediating drug resistance in bacteria, the inhibition of efflux pumps appears to be a promising strategy to restore antibacterial potency. In recent years, in order to address this grave problem of multiple drug resistance mediated by efflux pump, a large number of efflux pump inhibitors have been discovered and tested, including natural products, antibiotics and synthetic molecules. This review mainly describes recent achievements in the search for new molecules that are able to inhibit efflux pumps in both Gram-positive and Gram-negative bacteria, in particular emphasis on natural and synthetic inhibitors of the NorA efflux pump in Staphylococcus aureus, MexAB-OprM efflux pump in Pseudomonas aeruginosa, and AcrAB-TolC efflux pump in Enterobacteriaceae, giving special attention to their mechanisms of action, structure-activity relationships and synergetic effect with clinically available antibiotics.
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Rapid increase of multidrug resistance in bacteria has made the discovery of new antimicrobials necessary. From the time of discovery of bacterial efflux pumps in 1980, many bacteria have been characterized as multi drug resistant. Efflux pumps expel out the antibiotics and other resistance modifying compounds and dyes. Antibiotic resistance developed very quickly due to the changes in expression of efflux pumps. Mechanism of efflux has wildly known as major constituent of resistance in many classes of antibiotics. Multidrug resistance related to efflux is a major factor by which bacteria lowers the effect of antibacterial agents. It is therefore necessary that new antibiotics and efflux pump inhibitor are discovered. The bacterial efflux pump inhibitor helps in the reuse of antibiotics which are therapeutically ineffective. In the present study we study 15 medicinal plants for their efflux pump inhibitory activity against E. coli bacteria.
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Resistance of bacteria to most of the classes of antibiotics is a big problem now days. The component responsible for resistance in both the gram positive and gram negative bacteria are classified as multidrug resistant efflux pumps. In recent years a huge number of efflux pumps are identified in both gram- positive and gram- negative bacteria and these efflux pumps are responsible for the intrinsic resistance of bacteria to most of the antibiotics. Efflux pump inhibitors are the compounds which inhibit the activity of efflux pumps and they have the potential to restore the activity of standard antibiotics. In recent years, there are many classes of efflux pump inhibitors has been reported. Some of these efflux pump inhibitors are synthetic while some of them are natural inhibitors. Efflux pump inhibitors derived from chemical sources have drawbacks as they shows toxic effect at high concentrations in which they can be used. Some plants show potential EPI activity along with some antibiotics and shows effect on many efflux pumps. This review focuses on the use of efflux pump inhibitors from natural sources for blocking the activity of efflux pumps in case of both gram positive and gram negative bacteria.
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Abstract Bacteria have developed resistance to antibiotics by various mechanisms, notable amongst these is the use of permeation barriers and the expulsion of antibiotics via efflux pumps. The resistance-nodulation-division (RND) family of efflux pumps is found in Gram-negative bacteria and a major contributor to multidrug resistance (MDR). In particular, Salmonella encodes five RND efflux pump systems: AcrAB, AcrAD, AcrEF, MdsAB and MdtAB which have different substrate ranges including many antibiotics. We produce a spatial partial differential equation (PDE) model governing the diffusion and efflux of antibiotic in Salmonella , via these RND efflux pumps. Using parameter fitting techniques on experimental data, we are able to establish the behaviour of multiple wild-type and efflux mutant Salmonella strains, which enables us to produce efflux profiles for each individual efflux pump system. By combining the model with a gene regulatory network (GRN) model of efflux regulation, we simulate how the bacteria respond to their environment. Finally, performing a parameter sensitivity analysis, we look into various different targets to inhibit the efflux pumps. The model provides an in silico framework with which to test these potential adjuvants to counter MDR.
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Resistance of bacteria to many classes of antibiotics is an increasing problem worldwide. Multidrug resistance efflux pumps are recognized as an important component of resistance in both Gram-positive and Gram-negative bacteria. Some bacterial efflux pumps may be selective for one substrate, such as tetracycline, or transport antibiotics of different classes, conferring a multiple drug resistance (MDR) phenotype. Efflux pump inhibitors (EPIs) are promising therapeutic agents, as they should restore the activity of standard antibiotics. The efflux pump inhibitor-antibiotic combination is expected to increase the intracellular concentration of antibiotics that are expelled by efflux pumps, decrease the intrinsic bacterial resistance to antibiotics, reverse the acquired resistance associated with efflux pumps overexpression, and reduce the frequency of the emergence of resistant mutant strains. In recent years, different classes of EPIs have been described and tested, including analogues of antibiotic substrates and new molecules. This review focuses on the families of MDR efflux pumps, and on the current progress for the clinical use of EPIs. The present article is a good review of the recent patents related to efflux pump inhibitors. Keywords: Bacterial resistance, multidrug resistance, antibiotic efflux, efflux system, efflux pump inhibitors
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