scholarly journals On the role of TolC in multidrug efflux: the function and assembly of AcrAB-TolC tolerate significant depletion of intracellular TolC protein

2013 ◽  
Vol 87 (5) ◽  
pp. 982-997 ◽  
Author(s):  
Ganesh Krishnamoorthy ◽  
Elena B. Tikhonova ◽  
Girija Dhamdhere ◽  
Helen I. Zgurskaya
Keyword(s):  
Multidrug Efflux ◽  
Tolc Protein

scholarly journals Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation

2013 ◽  
Vol 7 (1) ◽  
pp. 34-52 ◽  
Author(s):  
Christina Kourtesi ◽  
Anthony R Ball ◽  
Ying-Ying Huang ◽  
Sanjay M Jachak ◽  
D Mariano A Vera ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Major Theme ◽  
Clinical Implementation ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Development Path ◽  
Microbial Infections ◽  
Efflux Pump Inhibitors ◽  
Shed Light

Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches.

scholarly journals Magnitude of Voriconazole Resistance in Clinical and Environmental Isolates of Aspergillus flavus and Investigation into the Role of Multidrug Efflux Pumps

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Raees A. Paul ◽  
Shivaprakash M. Rudramurthy ◽  
Manpreet Dhaliwal ◽  
Pankaj Singh ◽  
Anup K. Ghosh ◽  
...  
Keyword(s):  
Aspergillus Flavus ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Azole Resistance ◽  
Wild Type ◽  
Multidrug Efflux ◽  
Environmental Isolates ◽  
Content Type ◽  
Multidrug Efflux Pumps

ABSTRACT The magnitude of azole resistance in Aspergillus flavus and its underlying mechanism is obscure. We evaluated the frequency of azole resistance in a collection of clinical (n = 121) and environmental isolates (n = 68) of A. flavus by the broth microdilution method. Six (5%) clinical isolates displayed voriconazole MIC greater than the epidemiological cutoff value. Two of these isolates with non-wild-type MIC were isolated from same patient and were genetically distinct, which was confirmed by amplified fragment length polymorphism analysis. Mutations associated with azole resistance were not present in the lanosterol 14-α demethylase coding genes (cyp51A, cyp51B, and cyp51C). Basal and voriconazole-induced expression of cyp51A homologs and various efflux pump genes was analyzed in three each of non-wild-type and wild-type isolates. All of the efflux pump genes screened showed low basal expression irrespective of the azole susceptibility of the isolate. However, the non-wild-type isolates demonstrated heterogeneous overexpression of many efflux pumps and the target enzyme coding genes in response to induction with voriconazole (1 μg/ml). The most distinctive observation was approximately 8- to 9-fold voriconazole-induced overexpression of an ortholog of the Candida albicans ATP binding cassette (ABC) multidrug efflux transporter, Cdr1, in two non-wild-type isolates compared to those in the reference strain A. flavus ATCC 204304 and other wild-type strains. Although the dominant marker of azole resistance in A. flavus is still elusive, the current study proposes the possible role of multidrug efflux pumps, especially that of Cdr1B overexpression, in contributing azole resistance in A. flavus.

scholarly journals Role of TMS5: staphylococcal multidrug-efflux protein QacA

2008 ◽  
Vol 121 (5) ◽  
pp. 409-413 ◽  
Author(s):  
Bei JIA ◽  
Ting-quan ZHOU ◽  
Ai-long HUANG ◽  
Wen-xiang HUANG
Keyword(s):  
Multidrug Efflux

scholarly journals Role of the AheABC Efflux Pump in Aeromonas hydrophila Intrinsic Multidrug Resistance

2008 ◽  
Vol 52 (4) ◽  
pp. 1559-1563 ◽  
Author(s):  
Mathieu Hernould ◽  
Séverine Gagné ◽  
Michel Fournier ◽  
Claudine Quentin ◽  
Corinne Arpin
Keyword(s):  
Multidrug Resistance ◽  
Aeromonas Hydrophila ◽  
Efflux Pump ◽  
Gene Inactivation ◽  
Multidrug Efflux ◽  
Intrinsic Resistance

ABSTRACT Gene inactivation and complementation experiments showed that the tripartite AheABC efflux pump of Aeromonas hydrophila extruded at least 13 substrates, including nine antibiotics. The use of phenylalanine-arginine-β-naphthylamide (PAβN) revealed an additional system(s) contributing to intrinsic resistance. This is the first analysis of the role of multidrug efflux systems in Aeromonas spp.

scholarly journals Resistance to pentamidine is mediated by AdeAB, regulated by AdeRS, and influenced by growth conditions inAcinetobacter baumanniiATCC 17978

2018 ◽  
Author(s):  
Felise G. Adams ◽  
Uwe H. Stroeher ◽  
Karl A. Hassan ◽  
Shashikanth Marri ◽  
Melissa H. Brown
Keyword(s):  
Signal Transduction ◽  
Antimicrobial Resistance ◽  
Carbon Sources ◽  
Growth Conditions ◽  
Multidrug Efflux ◽  
Intrinsic Resistance ◽  
Multidrug Efflux Pumps ◽  
Two Component ◽  
Two Component Signal Transduction

AbstractIn recent years, effective treatment of infections caused byAcinetobacter baumanniihas become challenging due to the ability of the bacterium to acquire or up-regulate antimicrobial resistance determinants. Two component signal transduction systems are known to regulate expression of virulence factors including multidrug efflux pumps. Here, we investigated the role of the AdeRS two component signal transduction system in regulating the AdeAB efflux system, determined whether AdeA and/or AdeB can individually confer antimicrobial resistance, and explored the interplay between pentamidine resistance and growth conditions inA. baumanniiATCC 17978. Results identified that deletion ofadeRSaffected resistance towards chlorhexidine and 4’,6-diamidino-2-phenylindole dihydrochloride, two previously defined AdeABC substrates, and also identified an 8-fold decrease in resistance to pentamidine. Examination of ΔadeA, ΔadeBand ΔadeABcells augmented results seen for ΔadeRSand identified a set of dicationic AdeAB substrates. RNA-sequencing of ΔadeRSrevealed transcription of 290 genes were ≥2-fold altered compared to the wildtype. Pentamidine shock significantly increasedadeAexpression in the wildtype, but decreased it in ΔadeRS, implying that AdeRS activatesadeABtranscription in ATCC 17978. Investigation under multiple growth conditions, including the use of Biolog phenotypic microarrays, revealed resistance to pentamidine in ATCC 17978 and mutants could be altered by bioavailability of iron or utilization of different carbon sources. In conclusion, the results of this study provide evidence that AdeAB in ATCC 17978 can confer intrinsic resistance to a subset of dicationic compounds and in particular, resistance to pentamidine can be significantly altered depending on the growth conditions.

scholarly journals The role of the TolC family in protein transport and multidrug efflux.

2001 ◽  
Vol 268 (19) ◽  
pp. 5011-5026 ◽  
Author(s):  
Andrew Sharff ◽  
Cristina Fanutti ◽  
Jiye Shi ◽  
Chris Calladine ◽  
Ben Luisi
Keyword(s):  
Protein Transport ◽  
Multidrug Efflux

scholarly journals Role of VltAB, an ABC Transporter Complex, in Viologen Tolerance inStreptococcus mutans

2011 ◽  
Vol 55 (4) ◽  
pp. 1460-1469 ◽  
Author(s):  
Saswati Biswas ◽  
Indranil Biswas
Keyword(s):  
Abc Transporter ◽  
Efflux Pump ◽  
Ammonium Compound ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Antibiotic Resistance Marker ◽  
Gram Positive ◽  
Wide Range ◽  
Insertion Mutants

ABSTRACTStreptococcus mutans, a Gram-positive organism, is the primary causative agent in the formation of dental caries in humans. To persist in the oral cavity,S. mutansmust be able to tolerate rapid environmental fluctuations and exposure to various toxic chemicals. However, the mechanisms underlying the ability of this cariogenic pathogen to survive and proliferate under harsh environmental conditions remain largely unknown. Here, we wanted to understand the mechanisms by whichS. mutanswithstands exposure to methyl viologen (MV), a quaternary ammonium compound (QAC) that generates superoxide radicals in the cell. To elucidate the essential genes for MV tolerance, screening of ∼3,500 mutants generated by ISS1mutagenesis, revealed 15 MV-sensitive mutants. Among them, five and four independent insertions had occurred in SMU.905 and SMU.906 genes, respectively. These two genes are appeared to be organized in an operon and encode a putative ABC transporter complex; we designated the genes asvltAandvltB, forviologentransporter. To verify our results,vltAwas deleted by using an antibiotic resistance marker; the mutant was just as sensitive to MV as the ISS1insertion mutants. Furthermore,vltAandvltBmutants were also sensitive to other viologen compounds such as benzyl and ethyl viologens. Complementation assays were also carried out to confirm the role of VltA and VltB in viologen tolerance. Sensitivity to various drugs, including a wide range of QACs, was evaluated. It appears that a functional VltA is also required for full resistance toward acriflavin, ethidium bromide, and safranin; all are well-known QACs. These results indicate that VltA/B constitute a heterodimeric multidrug efflux pump of the ABC family. BLAST-P analysis suggests that homologs of VltA/B are widely present in streptococci, enterococci, and other important Gram-positive pathogens.

scholarly journals Characterization of a Unique Outer Membrane Protein Required for Oxidative Stress Resistance and Virulence of Francisella tularensis

2018 ◽  
Vol 200 (8) ◽  
Author(s):  
Maha Alqahtani ◽  
Zhuo Ma ◽  
Harshada Ketkar ◽  
Ragavan Varadharajan Suresh ◽  
Meenakshi Malik ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Membrane Protein ◽  
Outer Membrane ◽  
Francisella Tularensis ◽  
Efflux Pump ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Content Type

ABSTRACT Francisella tularensis , the causative agent of tularemia, lacks typical bacterial virulence factors and toxins but still exhibits extreme virulence. The bacterial multidrug efflux systems consist of an inner membrane, a transmembrane membrane fusion protein, and an outer membrane (OM) component that form a contiguous channel for the secretion of a multitude of bacterial products. Francisella contains three orthologs of the OM proteins; two of these, termed TolC and FtlC, are important for tularemia pathogenesis. The third OM protein, SilC, is homologous to the silver cation efflux protein of other bacterial pathogens. The silC gene ( FTL_0686 ) is located on an operon encoding an Emr-type multidrug efflux pump of F. tularensis . The role of SilC in tularemia pathogenesis is not known. In this study, we investigated the role of SilC in secretion and virulence of F. tularensis by generating a silC gene deletion (Δ silC ) mutant and its transcomplemented strain. Our results demonstrate that the Δ silC mutant exhibits increased sensitivity to antibiotics, oxidants, silver, diminished intramacrophage growth, and attenuated virulence in mice compared to wild-type F. tularensis . However, the secretion of antioxidant enzymes of F. tularensis is not impaired in the Δ silC mutant. The virulence of the Δ silC mutant is restored in NADPH oxidase-deficient mice, indicating that SilC resists oxidative stress in vivo . Collectively, this study demonstrates that the OM component SilC serves a specialized role in virulence of F. tularensis by conferring resistance against oxidative stress and silver. IMPORTANCE Francisella tularensis , the causative agent of a fatal human disease known as tularemia, is a category A select agent and a potential bioterror agent. The virulence mechanisms of Francisella are not completely understood. This study investigated the role of a unique outer membrane protein, SilC, of a multidrug efflux pump in the virulence of F. tularensis . This is the first report demonstrating that the OM component SilC plays an important role in efflux of silver and contributes to the virulence of F. tularensis primarily by providing resistance against oxidative stress. Characterization of these unique virulence mechanisms will provide an understanding of the pathogenesis of tularemia and identification of potential targets for the development of effective therapeutics and prophylactics for protection from this lethal disease.

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