scholarly journals Two Distinct Major Facilitator Superfamily Drug Efflux Pumps Mediate Chloramphenicol Resistance in Streptomyces coelicolor

2009 ◽  
Vol 53 (11) ◽  
pp. 4673-4677 ◽  
Author(s):  
James J. Vecchione ◽  
Blair Alexander ◽  
Jason K. Sello
Keyword(s):  
Efflux Pump ◽  
Streptomyces Coelicolor ◽  
Efflux Pumps ◽  
Major Facilitator Superfamily ◽  
Close Relative ◽  
Gram Positive ◽  
Antibacterial Drugs ◽  
Chloramphenicol Resistance ◽  
Drug Activity ◽  
Major Facilitator

ABSTRACT Chloramphenicol, florfenicol, and thiamphenicol are used as antibacterial drugs in clinical and veterinary medicine. Two efflux pumps of the major facilitator superfamily encoded by the cmlR1 and cmlR2 genes mediate resistance to these antibiotics in Streptomyces coelicolor, a close relative of Mycobacterium tuberculosis. The transcription of both genes was observed by reverse transcription-PCR. Disruption of cmlR1 decreased the chloramphenicol MIC 1.6-fold, while disruption of cmlR2 lowered the MIC 16-fold. The chloramphenicol MIC of wild-type S. coelicolor decreased fourfold and eightfold in the presence of reserpine and Phe-Arg-β-naphthylamide, respectively. These compounds are known to potentiate the activity of some antibacterial drugs via efflux pump inhibition. While reserpine is known to potentiate drug activity against gram-positive bacteria, this is the first time that Phe-Arg-β-naphthylamide has been shown to potentiate drug activity against a gram-positive bacterium.

scholarly journals Structural and Functional Study of the Phenicol-Specific Efflux Pump FloR Belonging to the Major Facilitator Superfamily

2005 ◽  
Vol 49 (7) ◽  
pp. 2965-2971 ◽  
Author(s):  
Martine Braibant ◽  
Jacqueline Chevalier ◽  
Elisabeth Chaslus-Dancla ◽  
Jean-Marie Pagès ◽  
Axel Cloeckaert
Keyword(s):  
Efflux Pump ◽  
Major Facilitator Superfamily ◽  
Site Directed Mutagenesis ◽  
Functional Study ◽  
Efflux Transporters ◽  
Chloramphenicol Resistance ◽  
Active Efflux ◽  
Transmembrane Segments ◽  
Efflux Mechanism ◽  
Major Facilitator

ABSTRACT The florfenicol-chloramphenicol resistance gene floR from Salmonella enterica was previously identified and postulated to belong to the major facilitator (MF) superfamily of drug exporters. Here, we confirmed a computer-predicted transmembrane topological model of FloR, using the phoA gene fusion method, and classified this protein in the DHA12 family (containing 12 transmembrane domains) of MF efflux transporters. We also showed that FloR is a transporter specific for structurally associated phenicol drugs (chloramphenicol, florfenicol, thiamphenicol) which utilizes the proton motive force to energize an active efflux mechanism. By site-directed mutagenesis of specific charged residues belonging to putative transmembrane segments (TMS), two residues essential for active efflux function, D23 in TMS1 and R109 in TMS4, were identified. Of these, the acidic residue D23 seems to participate directly in the affinity pocket involved in phenicol derivative recognition. A third residue, E283 in TMS9, seems to be necessary for correct membrane folding of the transporter.

scholarly journals The Varied Role of Efflux Pumps of the MFS Family in the Interplay of Bacteria with Animal and Plant Cells

2019 ◽  
Vol 7 (9) ◽  
pp. 285 ◽  
Author(s):  
Pasqua ◽  
Grossi ◽  
Zennaro ◽  
Fanelli ◽  
Micheli ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Major Facilitator Superfamily ◽  
Host Cells ◽  
Multidrug Efflux ◽  
Animal Cells ◽  
Multidrug Efflux Pumps ◽  
Wide Range ◽  
Major Facilitator

Efflux pumps represent an important and large group of transporter proteins found in all organisms. The importance of efflux pumps resides in their ability to extrude a wide range of antibiotics, resulting in the emergence of multidrug resistance in many bacteria. Besides antibiotics, multidrug efflux pumps can also extrude a large variety of compounds: Bacterial metabolites, plant-produced compounds, quorum-sensing molecules, and virulence factors. This versatility makes efflux pumps relevant players in interactions not only with other bacteria, but also with plant or animal cells. The multidrug efflux pumps belonging to the major facilitator superfamily (MFS) are widely distributed in microbial genomes and exhibit a large spectrum of substrate specificities. Multidrug MFS efflux pumps are present either as single-component transporters or as tripartite complexes. In this review, we will summarize how the multidrug MFS efflux pumps contribute to the interplay between bacteria and targeted host cells, with emphasis on their role in bacterial virulence, in the colonization of plant and animal host cells and in biofilm formation. We will also address the complexity of these interactions in the light of the underlying regulatory networks required for the effective activation of efflux pump genes.

scholarly journals Antimicrobial Activity of a Library of Thioxanthones and Their Potential as Efflux Pump Inhibitors

2021 ◽  
Vol 14 (6) ◽  
pp. 572
Author(s):  
Fernando Durães ◽  
Andreia Palmeira ◽  
Bárbara Cruz ◽  
Joana Freitas-Silva ◽  
Nikoletta Szemerédi ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Mammalian Cells ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Major Facilitator Superfamily ◽  
Design And Synthesis ◽  
Resistance Nodulation Division ◽  
Efflux Pump Inhibitors ◽  
Major Facilitator

The overexpression of efflux pumps is one of the causes of multidrug resistance, which leads to the inefficacy of drugs. This plays a pivotal role in antimicrobial resistance, and the most notable pumps are the AcrAB-TolC system (AcrB belongs to the resistance-nodulation-division family) and the NorA, from the major facilitator superfamily. In bacteria, these structures can also favor virulence and adaptation mechanisms, such as quorum-sensing and the formation of biofilm. In this study, the design and synthesis of a library of thioxanthones as potential efflux pump inhibitors are described. The thioxanthone derivatives were investigated for their antibacterial activity and inhibition of efflux pumps, biofilm formation, and quorum-sensing. The compounds were also studied for their potential to interact with P-glycoprotein (P-gp, ABCB1), an efflux pump present in mammalian cells, and for their cytotoxicity in both mouse fibroblasts and human Caco-2 cells. The results concerning the real-time ethidium bromide accumulation may suggest a potential bacterial efflux pump inhibition, which has not yet been reported for thioxanthones. Moreover, in vitro studies in human cells demonstrated a lack of cytotoxicity for concentrations up to 20 µM in Caco-2 cells, with some derivatives also showing potential for P-gp modulation.

scholarly journals Farnesol abrogates biofilm- and efflux pump- associated genes in drug resistant Candida auris strains

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Vartika Srivastava ◽  
Aijaz Ahmad
Keyword(s):  
Active Drug ◽  
Efflux Pump ◽  
Antifungal Susceptibility ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Major Facilitator Superfamily ◽  
Drug Efflux ◽  
Candida Auris ◽  
Efflux Mechanism ◽  
Major Facilitator

Background: Candida auris, a decade old Candida species, has been identified globally as a significant nosocomial multidrug resistant (MDR) pathogen responsible for causing invasive outbreaks. Biofilms and over expression of efflux pumps such as Major Facilitator Superfamily and ATP Binding Cassette are known to cause multidrug resistance in Candida species, including C. auris. Therefore, targeting these factors may prove an effective approach to combat MDR in C. auris. Methods: In this study, 25 clinical isolates of C. auris from different hospitals of South Africa were used. Antifungal susceptibility profile of all the isolates against commonly used drugs was determined following CLSI recommended guidelines. Rhodamine-6-G extracellular efflux and intracellular accumulation assays were used to study active drug efflux mechanism. We further studied the role of farnesol in modulating development of biofilms and drug efflux in C. auris. Down-regulation of biofilm- and efflux pump- associated genes by farnesol was also investigated. CLSM analysis for examining C. auris biofilm architecture among treated and untreated isolates. Results: Most of the isolates (twenty-two) were found resistant to FLZ whereas five were resistant to AmB. All the isolates were found capable of biofilm formation and ornamented with active drug efflux mechanism. The MIC for planktonic cells ranged from 62.5-125 mM and for sessile cells was 125 mM (0 h and 4 h biofilm) and 500 mM (12 h and 24 h biofilm), CLSM studies also confirmed these findings. Farnesol also blocked efflux pumps and down-regulated biofilm- and efflux pump- associated genes. Conclusion: Modulation of biofilm- and efflux pump- associated genes by farnesol represent a promising approach in combating C. auris infection.

scholarly journals Novel Florfenicol and Chloramphenicol Resistance Gene Discovered in Alaskan Soil by Using Functional Metagenomics

2010 ◽  
Vol 76 (15) ◽  
pp. 5321-5326 ◽  
Author(s):  
Kevin S. Lang ◽  
Janet M. Anderson ◽  
Stefan Schwarz ◽  
Lynn Williamson ◽  
Jo Handelsman ◽  
...  
Keyword(s):  
Resistance Gene ◽  
Resistance Genes ◽  
Efflux Pumps ◽  
Major Facilitator Superfamily ◽  
Functional Metagenomics ◽  
Chloramphenicol Resistance ◽  
Major Facilitator

ABSTRACT Functional metagenomics was used to search for florfenicol resistance genes in libraries of cloned DNA isolated from Alaskan soil. A gene that mediated reduced susceptibility to florfenicol was identified and designated pexA. The predicted PexA protein showed a structure similar to that of efflux pumps of the major facilitator superfamily.

scholarly journals Berberine reverses multidrug resistance in Candida albicans by hijacking the drug efflux pump Mdr1p

2020 ◽  
Author(s):  
Yaojun Tong ◽  
Nuo Sun ◽  
Xiangming Wang ◽  
Qi Wei ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Multidrug Resistance ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Major Facilitator Superfamily ◽  
Drug Efflux ◽  
Multidrug Efflux Pump ◽  
Drug Efflux Pumps ◽  
Major Facilitator

AbstractClinical use of antimicrobials faces great challenges from the emergence of multidrug resistant (MDR) pathogens. The overexpression of drug efflux pumps is one of the major contributors to MDR. It is considered as a promising approach to overcome MDR by reversing the function of drug efflux pumps. In the life-threatening fungal pathogen Candida albicans, the major facilitator superfamily (MFS) transporter Mdr1p can excrete many structurally unrelated antifungals, leading to multidrug resistance. Here we report a counterintuitive case of reversing multidrug resistance in C. albicans by using a natural product berberine to hijack the overexpressed Mdr1p for its own importation. Moreover, we illustrate that the imported berberine accumulates in mitochondria, and compromises the mitochondrial function by impairing mitochondrial membrane potential and mitochondrial Complex I. It results in the selective elimination of Mdr1p overexpressed C. albicans cells. Furthermore, we show that berberine treatment can prolong the mean survival time (MST) of mice with a blood-borne dissemination of Mdr1p overexpressed multidrug resistant candidiasis. This study provided a potential direction of novel anti-MDR drug discovery by screening for multidrug efflux pump converters.

scholarly journals CraA, a Major Facilitator Superfamily Efflux Pump Associated with Chloramphenicol Resistance in Acinetobacter baumannii

2009 ◽  
Vol 53 (9) ◽  
pp. 4013-4014 ◽  
Author(s):  
I. Roca ◽  
S. Marti ◽  
P. Espinal ◽  
P. Martínez ◽  
I. Gibert ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Acinetobacter Baumannii ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Major Facilitator Superfamily ◽  
Intrinsic Resistance ◽  
Chloramphenicol Resistance ◽  
Hospital Acquired Infections ◽  
Major Facilitator ◽  
Hospital Acquired

ABSTRACT Acinetobacter baumannii has been increasingly associated with hospital-acquired infections, and the presence of multidrug resistance strains is of great concern to clinicians. A. baumannii is thought to possess a great deal of intrinsic resistance to several antimicrobial agents, including chloramphenicol, although the mechanisms involved in such resistance are not well understood. In this work, we have identified a major facilitator superfamily efflux pump present in most A. baumannii strains, displaying strong substrate specificity toward chloramphenicol.

scholarly journals Efflux Pumps of Mycobacterium tuberculosis Play a Significant Role in Antituberculosis Activity of Potential Drug Candidates

2012 ◽  
Vol 56 (5) ◽  
pp. 2643-2651 ◽  
Author(s):  
Meenakshi Balganesh ◽  
Neela Dinesh ◽  
Sreevalli Sharma ◽  
Sanjana Kuruppath ◽  
Anju V. Nair ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Vital Role ◽  
Major Facilitator Superfamily ◽  
Content Type ◽  
Active Efflux ◽  
Drug Candidates ◽  
Small Multidrug Resistance ◽  
Major Facilitator

ABSTRACTActive efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. To understand these efflux mechanisms inMycobacterium tuberculosis, we generated knockout (KO) mutants of four efflux pumps of the pathogen belonging to different classes. We measured the MICs and kill values of two different compound classes on the wild type (WT) and the efflux pump (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil andl-phenylalanyl-l-arginyl-β-naphthylamide (PAβN). Among the pumps studied, the efflux pumps belonging to the ABC (ATP-binding cassette) class, encoded byRv1218c, and the SMR (small multidrug resistance) class, encoded byRv3065, appear to play important roles in mediating the efflux of different chemical classes and antibiotics. Efflux pumps encoded byRv0849andRv1258calso mediate the efflux of these compounds, but to a lesser extent. Increased killing is observed in WTM. tuberculosiscells by these compounds in the presence of either verapamil or PAβN. The efflux pump KO mutants were more susceptible to these compounds in the presence of efflux inhibitors. We have shown that these four efflux pumps ofM. tuberculosisplay a vital role in mediating efflux of different chemical scaffolds. Inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis. The identification and characterization ofRv0849, a new efflux pump belonging to the MFS (major facilitator superfamily) class, are reported.

Membrane homoeostasis and multidrug resistance in yeast

2008 ◽  
Vol 28 (4) ◽  
pp. 217-228 ◽  
Author(s):  
Sneh Lata Panwar ◽  
Ritu Pasrija ◽  
Rajendra Prasad
Keyword(s):  
Multidrug Resistance ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Membrane Lipid ◽  
Major Facilitator Superfamily ◽  
Drug Efflux ◽  
Proper Functioning ◽  
Drug Efflux Pumps ◽  
Drug Efflux Pump ◽  
Major Facilitator

The development of MDR (multidrug resistance) in yeast is due to a number of mechanisms. The most documented mechanism is enhanced extrusion of drugs mediated by efflux pump proteins belonging to either the ABC (ATP-binding cassette) superfamily or MFS (major facilitator superfamily). These drug-efflux pump proteins are localized on the plasma membrane, and the milieu therein affects their proper functioning. Several recent studies demonstrate that fluctuations in membrane lipid composition affect the localization and proper functioning of the MDR efflux pump proteins. Interestingly, the efflux pumps of the ABC superfamily are particularly susceptible to imbalances in membrane-raft lipid constituents. This review focuses on the importance of the membrane environment in functioning of the drug-efflux pumps and explores a correlation between MDR and membrane lipid homoeostasis.

scholarly journals Bifunctional Enzyme SpoT Is Involved in Biofilm Formation ofHelicobacter pyloriwith Multidrug Resistance by Upregulating Efflux Pump Hp1174 (gluP)

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Xiaoran Ge ◽  
Yuying Cai ◽  
Zhenghong Chen ◽  
Sizhe Gao ◽  
Xiwen Geng ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Major Facilitator Superfamily ◽  
Bifunctional Enzyme ◽  
Content Type ◽  
H Pylori ◽  
Major Facilitator

ABSTRACTThe drug resistance ofHelicobacter pyloriis gradually becoming a serious problem. Biofilm formation is an important factor that leads to multidrug resistance (MDR) in bacteria. The ability ofH. pylorito form biofilms on the gastric mucosa is known. However, there are few studies on the regulatory mechanisms ofH. pyloribiofilm formation and multidrug resistance. Guanosine 3′-diphosphate 5′-triphosphate and guanosine 3′,5′-bispyrophosphate [(p)ppGpp] are global regulatory factors and are synthesized inH. pyloriby the bifunctional enzyme SpoT. It has been reported that (p)ppGpp is involved in the biofilm formation and multidrug resistance of various bacteria. In this study, we found that SpoT also plays an important role inH. pyloribiofilm formation and multidrug resistance. Therefore, it was necessary to carry out some further studies regarding its regulatory mechanism. Considering that efflux pumps are of great importance in the biofilm formation and multidrug resistance of bacteria, we tried to determine whether efflux pumps controlled by SpoT participate in these activities. We found that Hp1174 (glucose/galactose transporter [gluP]), an efflux pump of the major facilitator superfamily (MFS), is highly expressed in biofilm-forming and multidrug-resistant (MDR)H. pyloristrains and is upregulated by SpoT. Through further research, we determined thatgluPis involved inH. pyloribiofilm formation and multidrug resistance. Furthermore, the average expression level ofgluPin the clinical MDR strains (C-MDR) was considerably higher than that in the clinical drug-sensitive strains (C-DSS). Taken together, our results revealed a novel molecular mechanism ofH. pyloriresistance to multidrug exposure.

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