scholarly journals Modulation of Bacterial Multidrug Resistance Efflux Pumps of the Major Facilitator Superfamily

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Sanath Kumar ◽  
Mun Mun Mukherjee ◽  
Manuel F. Varela
Keyword(s):  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Major Facilitator Superfamily ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Multidrug Efflux ◽  
Multidrug Resistant Bacteria ◽  
Multidrug Efflux Pumps ◽  
Clinical Resistance ◽  
Major Facilitator

Bacterial infections pose a serious public health concern, especially when an infectious disease has a multidrug resistant causative agent. Such multidrug resistant bacteria can compromise the clinical utility of major chemotherapeutic antimicrobial agents. Drug and multidrug resistant bacteria harbor several distinct molecular mechanisms for resistance. Bacterial antimicrobial agent efflux pumps represent a major mechanism of clinical resistance. The major facilitator superfamily (MFS) is one of the largest groups of solute transporters to date and includes a significant number of bacterial drug and multidrug efflux pumps. We review recent work on the modulation of multidrug efflux pumps, paying special attention to those transporters belonging primarily to the MFS.

scholarly journals Functional and Structural Roles of the Major Facilitator Superfamily Bacterial Multidrug Efflux Pumps

2020 ◽  
Vol 8 (2) ◽  
pp. 266 ◽  
Author(s):  
Sanath Kumar ◽  
Manjusha Lekshmi ◽  
Ammini Parvathi ◽  
Manisha Ojha ◽  
Nicholas Wenzel ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antimicrobial Agents ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Amino Acid Sequences ◽  
Major Facilitator Superfamily ◽  
Multidrug Efflux ◽  
Ion Translocation ◽  
Multidrug Efflux Pumps ◽  
Major Facilitator

Pathogenic microorganisms that are multidrug-resistant can pose severe clinical and public health concerns. In particular, bacterial multidrug efflux transporters of the major facilitator superfamily constitute a notable group of drug resistance mechanisms primarily because multidrug-resistant pathogens can become refractory to antimicrobial agents, thus resulting in potentially untreatable bacterial infections. The major facilitator superfamily is composed of thousands of solute transporters that are related in terms of their phylogenetic relationships, primary amino acid sequences, two- and three-dimensional structures, modes of energization (passive and secondary active), and in their mechanisms of solute and ion translocation across the membrane. The major facilitator superfamily is also composed of numerous families and sub-families of homologous transporters that are conserved across all living taxa, from bacteria to humans. Members of this superfamily share several classes of highly conserved amino acid sequence motifs that play essential mechanistic roles during transport. The structural and functional importance of multidrug efflux pumps that belong to the major facilitator family and that are harbored by Gram-negative and -positive bacterial pathogens are considered here.

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.

Bacterial Multidrug Efflux Pumps of the Major Facilitator Superfamily as Targets for Modulation

2016 ◽  
Vol 16 (1) ◽  
pp. 28-43 ◽  
Author(s):  
Sanath Kumar ◽  
Guixin He ◽  
Prathusha Kakarla ◽  
Ugina Shrestha ◽  
Ranjana KC ◽  
...  
Keyword(s):  
Efflux Pumps ◽  
Major Facilitator Superfamily ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pumps ◽  
Major Facilitator

Bacterial Multidrug Efflux Pumps of the Major Facilitator Superfamily as Targets for Modulation

2016 ◽  
Vol 16 (999) ◽  
pp. 1-1
Author(s):  
Sanath Kumar ◽  
Guixin He ◽  
Prathusha Kakarla ◽  
Ugina Shrestha ◽  
KC Ranjana ◽  
...  
Keyword(s):  
Efflux Pumps ◽  
Major Facilitator Superfamily ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pumps ◽  
Major Facilitator

scholarly journals Function and Inhibitory Mechanisms of Multidrug Efflux Pumps

2021 ◽  
Vol 12 ◽  
Author(s):  
Kunihiko Nishino ◽  
Seiji Yamasaki ◽  
Ryosuke Nakashima ◽  
Martijn Zwama ◽  
Mitsuko Hayashi-Nishino
Keyword(s):  
Efflux Pump ◽  
Efflux Pumps ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Bacterial Cells ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Inhibitory Mechanisms ◽  
Multidrug Efflux Pumps ◽  
Multiple Antibiotics

Multidrug efflux pumps are inner membrane transporters that export multiple antibiotics from the inside to the outside of bacterial cells, contributing to bacterial multidrug resistance (MDR). Postgenomic analysis has demonstrated that numerous multidrug efflux pumps exist in bacteria. Also, the co-crystal structural analysis of multidrug efflux pumps revealed the drug recognition and export mechanisms, and the inhibitory mechanisms of the pumps. A single multidrug efflux pump can export multiple antibiotics; hence, developing efflux pump inhibitors is crucial in overcoming infectious diseases caused by multidrug-resistant bacteria. This review article describes the role of multidrug efflux pumps in MDR, and their physiological functions and inhibitory mechanisms.

scholarly journals Multidrug Efflux Pumps in Staphylococcus aureus: an Update

2013 ◽  
Vol 7 (1) ◽  
pp. 59-71 ◽  
Author(s):  
Sofia Santos Costa ◽  
Miguel Viveiros ◽  
Leonard Amaral ◽  
Isabel Couto
Keyword(s):  
Staphylococcus Aureus ◽  
Potential Role ◽  
Antimicrobial Agents ◽  
Defense Mechanism ◽  
Current Knowledge ◽  
Efflux Pumps ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pumps

The emergence of infections caused by multi- or pan-resistant bacteria in the hospital or in the community settings is an increasing health concern. Albeit there is no single resistance mechanism behind multiresistance, multidrug efflux pumps, proteins that cells use to detoxify from noxious compounds, seem to play a key role in the emergence of these multidrug resistant (MDR) bacteria. During the last decades, experimental data has established their contribution to low level resistance to antimicrobials in bacteria and their potential role in the appearance of MDR phenotypes, by the extrusion of multiple, unrelated compounds. Recent studies suggest that efflux pumps may be used by the cell as a first-line defense mechanism, avoiding the drug to reach lethal concentrations, until a stable, more efficient alteration occurs, that allows survival in the presence of that agent.In this paper we review the current knowledge on MDR efflux pumps and their intricate regulatory network inStaphylococcus aureus, a major pathogen, responsible from mild to life-threatening infections. Particular emphasis will be given to the potential role thatS. aureusMDR efflux pumps, either chromosomal or plasmid-encoded, have on resistance towards different antimicrobial agents and on the selection of drug - resistant strains. We will also discuss the many questions that still remain on the role of each specific efflux pump and the need to establish appropriate methodological approaches to address all these questions.

scholarly journals Inhibitors of Bacterial Multidrug Efflux Pumps Potentiate Antimicrobial Photoinactivation

2008 ◽  
Vol 52 (9) ◽  
pp. 3202-3209 ◽  
Author(s):  
George P. Tegos ◽  
Kayo Masago ◽  
Fatima Aziz ◽  
Andrew Higginbotham ◽  
Frank R. Stermitz ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Red Light ◽  
Antimicrobial Effect ◽  
Efflux Pumps ◽  
Photodynamic Inactivation ◽  
Multidrug Efflux ◽  
Efflux Pump Inhibitor ◽  
Multidrug Efflux Pumps ◽  
Resistance Nodulation Division ◽  
Major Facilitator

ABSTRACT Antimicrobial photodynamic inactivation (APDI) combines a nontoxic photoactivatable dye or photosensitizer (PS) with harmless visible light to generate singlet oxygen and reactive oxygen species that kill microbial cells. Cationic phenothiazinium dyes, such as toluidine blue O (TBO), are the only PS used clinically for APDI, and we recently reported that this class of PS are substrates of multidrug efflux pumps in both gram-positive and gram-negative bacteria. We now report that APDI can be significantly potentiated by combining the PS with an efflux pump inhibitor (EPI). Killing of Staphylococcus aureus mediated by TBO and red light is greatly increased by coincubation with known inhibitors of the major facilitator pump (NorA): the diphenyl urea INF271, reserpine, 5′-methoxyhydnocarpin, and the polyacylated neohesperidoside, ADH7. The potentiation effect is greatest in the case of S. aureus mutants that overexpress NorA and least in NorA null cells. Addition of the EPI before TBO has a bigger effect than addition of the EPI after TBO. Cellular uptake of TBO is increased by EPI. EPI increased photodynamic inactivation killing mediated by other phenothiazinium dyes, such as methylene blue and dimethylmethylene blue, but not that mediated by nonphenothiazinium PS, such as Rose Bengal and benzoporphyrin derivative. Killing of Pseudomonas aeruginosa mediated by TBO and light was also potentiated by the resistance nodulation division pump (MexAB-OprM) inhibitor phenylalanine-arginine beta-naphthylamide but to a lesser extent than for S. aureus. These data suggest that EPI could be used in combination with phenothiazinium salts and light to enhance their antimicrobial effect against localized infections.

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.

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