Molecular insights into the differential efflux mechanism of Rv1634 protein, a multidrug transporter of major facilitator superfamily in Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Garima Singh ◽  
Yusuf Akhter
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Protein A ◽  
Major Facilitator Superfamily ◽  
Multidrug Transporter ◽  
Efflux Mechanism ◽  
Major Facilitator

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 Multidrug Transporters Belonging to Major Facilitator Superfamily (MFS) in Mycobacterium tuberculosis

2002 ◽  
Vol 8 (11) ◽  
pp. 714-724 ◽  
Author(s):  
Edda De Rossi ◽  
Patrizio Arrigo ◽  
Marco Bellinzoni ◽  
Pedro E. A. Silva ◽  
Carlos Martin ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Major Facilitator Superfamily ◽  
Multidrug Transporters ◽  
Major Facilitator

scholarly journals No Single Irreplaceable Acidic Residues in the Escherichia coli Secondary Multidrug Transporter MdfA

2006 ◽  
Vol 188 (15) ◽  
pp. 5635-5639 ◽  
Author(s):  
Nadejda Sigal ◽  
Shahar Molshanski-Mor ◽  
Eitan Bibi
Keyword(s):  
Escherichia Coli ◽  
Critical Role ◽  
Energy Coupling ◽  
Major Facilitator Superfamily ◽  
Multidrug Transporter ◽  
Coupling Mechanism ◽  
Acidic Residues ◽  
Major Facilitator ◽  
Mfs Transporters ◽  
Solute Transporters

ABSTRACT The largest family of solute transporters (major facilitator superfamily [MFS]) includes proton-motive-force-driven secondary transporters. Several characterized MFS transporters utilize essential acidic residues that play a critical role in the energy-coupling mechanism during transport. Surprisingly, we show here that no single acidic residue plays an irreplaceable role in the Escherichia coli secondary multidrug transporter MdfA.

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 Identification of CTL Epitopes on Efflux Pumps of the ATP-Binding Cassette and the Major Facilitator Superfamily of Mycobacterium tuberculosis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yan Lin ◽  
Yu Dong ◽  
Yanfeng Gao ◽  
Ranran Shi ◽  
Yubing Li ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Lymphocyte ◽  
Efflux Pumps ◽  
Genetically Engineered ◽  
Major Facilitator Superfamily ◽  
Atp Binding ◽  
Drug Resistant ◽  
Genetically Engineered Mice ◽  
Major Facilitator ◽  
Atp Binding Cassette

Tuberculosis is the world’s most deadly infectious disease, with 10 million people falling ill and 1.5 million people dying from the disease every year. With the increasing number of drug-resistant Mycobacterium tuberculosis (MTB) strains and prevalence of coinfection of MTB with human immunodeficiency virus, many challenges remain in the prevention and treatment of tuberculosis. Therefore, the development of safe and effective tuberculosis vaccines is an urgent issue. In this study, we identified cytotoxic T lymphocyte epitopes on drug resistance-associated membrane protein efflux pumps of MTB, the ATP-binding cassette and the major facilitator superfamilies. First, three online software were used to predict HLA-A2-restricted epitopes. Then, the candidate epitopes were confirmed with the T2A2 cell binding affinity and peptide/MHC (pMHC) complex stability assays and in vitro immune activity experiments. Two drug-resistant T lymphocyte epitopes, designated Rv1218c-p24 and Rv2477c-p182, were selected, and their immunogenic activities studied in vivo in genetically engineered mice. The immune activities of these two epitopes were improved with the help of complete Freund’s adjuvant (CFA). The epitopes identified here provide a foundation for the diagnosis and treatment of patients infected with drug resistant and the future development of a multiepitope vaccine.

Mycobacterium tuberculosis Major Facilitator Superfamily Transporters

2017 ◽  
Vol 250 (6) ◽  
pp. 573-585 ◽  
Author(s):  
Ping Li ◽  
Yinzhong Gu ◽  
Jiang Li ◽  
Longxiang Xie ◽  
Xue Li ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Major Facilitator Superfamily ◽  
Major Facilitator

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.

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