Transcriptomic Responses of Bacterial Cells to Sublethal Metal Ion Stress
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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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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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AcrAB-TolC is a resistance nodulation division type of efflux pump present in Enterobacteriaceae. It non-specifically effluxes antibiotics out of the bacterial cell, thus conferring drug resistance. Increase in the expression of the AcrAB-TolC efflux pump increases resistance to antibiotics. We aimed to study the expression levels of acrA and acrB that encodes AcrAB-TolC efflux pump, to understand efflux pump mediated resistance to carbapenem among clinical isolates of Enterobacteriaceae obtained from various clinical samples. Additionally, co -production of carbapenemase was also detected in the isolates demonstrating efflux pump mediated resistance to carbapenems. A total of 127 carbapenem resistant clinical isolates of Enterobacteriaceae, isolated from a tertiary care hospital were included in the study. An efflux pump inhibition (EPI) assay with reserpine, an efflux pump inhibitor, was performed to screen for isolates exhibiting efflux pump activity. Real Time Reverse Transcriptase qPCR was performed to detect the mRNA over expression levels of acrA and acrB that encodes AcrAB-TolC efflux pump. The control strains K. pneumoniae BAA2146 and E. coli AcrB were used. EPI assay with carbapenem showed that 56 /127(44%) isolates were screen positive indicating efflux pump activity. A total of 12 isolates showed 101 to 107 increase in the expression of both acrA and acrB when compared with the controls indicating a strong efflux pump activity, in addition to producing carbapenemase. The study highlights the role of efflux pump AcrAB-TolC in conferring resistance to carbapenem among clinical isolates of Enterobacteriaceae.
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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.
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Over-expression of efflux pumps is one of the mechanisms causing multidrug resistant bacteria.It is necessary to clearly decipher this transport system from the genetic,structural,and functional aspects in order to combat this poly-selective mechanism.By understanding how efflux pumps work,we may be able to find a new group of antibacterial agents,termed efflux reversals,including membrane permeabilisers,efflux pump inhibitors and flux-competitive agents,specific blockers,energy poisons,etc.Several chemical families of efflux pump inhibitors have been described and characterized.This new family of molecules represents the first antibacterial class of compound specifically targeting active transport in the bacterial cell.
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Efflux pump; Inhibitor; Multidrug resistance
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