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Mechanistic and Structural Insights Into the Unique TetR-Dependent Regulation of a Drug Efflux Pump in Mycobacterium abscessus

Overview of attention for article published in Frontiers in Microbiology, April 2018
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Title
Mechanistic and Structural Insights Into the Unique TetR-Dependent Regulation of a Drug Efflux Pump in Mycobacterium abscessus
Published in
Frontiers in Microbiology, April 2018
DOI 10.3389/fmicb.2018.00649
Pubmed ID
Authors

Matthias Richard, Ana Victoria Gutiérrez, Albertus J. Viljoen, Eric Ghigo, Mickael Blaise, Laurent Kremer

Abstract

Mycobacterium abscessus is an emerging human pathogen causing severe pulmonary infections and is refractory to standard antibiotherapy, yet few drug resistance mechanisms have been reported in this organism. Recently, mutations in MAB_4384 leading to up-regulation of the MmpS5/MmpL5 efflux pump were linked to increased resistance to thiacetazone derivatives. Herein, the DNA-binding activity of MAB_4384 was investigated by electrophoretic mobility shift assays using the palindromic sequence IRS5/L5 located upstream of mmpS5/mmpL5. Introduction of point mutations within IRS5/L5 identified the sequence requirements for optimal binding of the regulator. Moreover, formation of the protein/IRS5/L5 complex was severely impaired for MAB_4384 harboring D14N or F57L substitutions. IRS5/L5/lacZ reporter fusions in M. abscessus demonstrated increased β-galactosidase activity either in strains lacking a functional MAB_4384 or in cultures treated with the TAC analogs. In addition, X-ray crystallography confirmed a typical TetR homodimeric structure of MAB_4384 and unraveled a putative ligand binding site in which the analogs could be docked. Overall, these results support drug recognition of the MAB_4384 TetR regulator, alleviating its binding to IRS5/L5 and steering up-regulation of MmpS5/MmpL5. This study provides new mechanistic and structural details of TetR-dependent regulatory mechanisms of efflux pumps and drug resistance in mycobacteria.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 59 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 59 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 13 22%
Student > Master 7 12%
Student > Ph. D. Student 7 12%
Student > Bachelor 5 8%
Student > Doctoral Student 3 5%
Other 5 8%
Unknown 19 32%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 17 29%
Immunology and Microbiology 6 10%
Chemistry 6 10%
Medicine and Dentistry 3 5%
Environmental Science 2 3%
Other 5 8%
Unknown 20 34%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 April 2018.
All research outputs
#20,481,952
of 23,043,346 outputs
Outputs from Frontiers in Microbiology
#22,768
of 25,186 outputs
Outputs of similar age
#291,049
of 329,683 outputs
Outputs of similar age from Frontiers in Microbiology
#542
of 602 outputs
Altmetric has tracked 23,043,346 research outputs across all sources so far. This one is in the 1st percentile – i.e., 1% of other outputs scored the same or lower than it.
So far Altmetric has tracked 25,186 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.3. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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We're also able to compare this research output to 602 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.