Rifampicin Reduces Susceptibility to Ofloxacin in Rifampicin-resistant Mycobacterium tuberculosis through Efflux
Gail E. Louw,Robin M. Warren,Nicolaas C. Gey van Pittius,Rosalba Leon,Adelina Jimenez,Rogelio Hernández-Pando,Christopher R.E. McEvoy,Melanie Grobbelaar,Megan Murray,Paul D. van Helden,Thomas C. Victor +10 more
Reads0
Chats0
TLDR
Exposure of rifampicin resistant M. tuberculosis strains to rifampsicin can potentially compromise the efficacy of the second-line treatment regimens containing ofloxacin, thereby emphasising the need for rapid diagnostics to guide treatment.Abstract:
Rationale: Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations.Objective: To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility.Methods: Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture in BACTEC 12B medium. Verapamil and reserpine were included to determine their effect on rifampicin and ofloxacin susceptibility. RT-qPCR was applied to assess expression of efflux pump/transporter genes after rifampicin exposure. To determine whether verapamil could restore susceptibility to first-line drugs, BALB/c mice were infected with a MDR-TB strain and treated with first-line drugs with/without verapamil.Measurements and Main Findings: Rifampicin MICs varied independently of rpoB mutation and genetic background. Addition reserp...read more
Citations
More filters
Journal ArticleDOI
Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c
Kawaljit Singh,Malkeet Kumar,Malkeet Kumar,Elumalai Pavadai,Elumalai Pavadai,Krupa Naran,Digby F. Warner,Peter G. Ruminski,Kelly Chibale,Kelly Chibale +9 more
TL;DR: Molecular docking studies of the binding sites of Rv1258c, a M. tuberculosis efflux protein previously implicated in intrinsic resistance to RIF, suggested a potential rationale for the superior synergistic interactions observed with some analogues.
Journal ArticleDOI
Dithiazole thione derivative as competitive NorA efflux pump inhibitor to curtail multi drug resistant clinical isolate of MRSA in a zebrafish infection model.
Rene Christena Lowrence,Thiagarajan Raman,Himesh Makala,Venkatasubramanian Ulaganathan,Selva Ganesan Subramaniapillai,Ashok Ayyappa Kuppuswamy,Anisha Mani,Sundaresan Chittoor Neelakantan,Saisubramanian Nagarajan +8 more
TL;DR: A novel non-toxic, non-haemolytic dithiazole thione derivative (DTT10) was identified as a potent competitive inhibitor of NorA efflux pump in S. aureus using in silico, in vitro and in vivo studies.
Journal ArticleDOI
Novel adjunctive therapies for the treatment of tuberculosis.
Alvaro A. Ordonez,Mamoudou Maiga,Shashank Gupta,Edward A. Weinstein,William R. Bishai,Sanjay K. Jain +5 more
TL;DR: Significant advances are being made in the development of shorter and effective TB drug regimens and there is growing evidence that host-directed and "non-antimicrobial" pathogen-directed therapies, could serve as novel approaches to enhance TB treatments.
BookDOI
Preface.Pathogenesis of Mycobacterium tuberculosis and its interaction with the host organism.
Jean Pieters,John D. McKinney +1 more
TL;DR: A Single-Cell Perspective on Non-Growing but Metabolically Active (NGMA) Bacteria Giulia Manina and John D. McKinney Mycobacterium tuberculosis Metabolism and Host Interaction: Mysteries and Paradoxes Sabine Ehrt and Kyu Rhee Surviving the Macrophage: Tools and Tricks Employed by MyCobacterial Protein Secretion as discussed by the authors.
Journal ArticleDOI
Mycobacterium tuberculosis Major Facilitator Superfamily Transporters
TL;DR: The structural properties and functions of M. tuberculosis MFS transporters, molecular mechanisms of substrates transfer, and efflux pump inhibitors are summarized for better control of biofilm-associated infections.
References
More filters
Journal ArticleDOI
Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence
Stewart T. Cole,Roland Brosch,Julian Parkhill,Thierry Garnier,Carol Churcher,David Harris,Stephen V. Gordon,Karin Eiglmeier,S. Gas,Clifton E. Barry,Fredj Tekaia,K. Badcock,D. Basham,D. Brown,Tracey Chillingworth,R. Connor,Robert L. Davies,K. Devlin,Theresa Feltwell,S. Gentles,N. Hamlin,S. Holroyd,T. Hornsby,Kay Jagels,Anders Krogh,J. McLean,Sharon Moule,Lee Murphy,K. Oliver,J. Osborne,Michael A. Quail,Marie-Adèle Rajandream,Jane Rogers,S. Rutter,K. Seeger,Jason Skelton,Rob Squares,S. Squares,John Sulston,K. Taylor,Sally Whitehead,Bart Barrell +41 more
TL;DR: The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve the understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions.
Journal ArticleDOI
Structural Mechanism for Rifampicin Inhibition of Bacterial RNA Polymerase
Elizabeth A. Campbell,Nataliya Korzheva,Arkady Mustaev,Katsuhiko S. Murakami,Satish K. Nair,Alex Goldfarb,Seth A. Darst +6 more
TL;DR: The crystal structure of Thermus aquaticus core RNAP complexed with Rif explains the effects of Rif on RNAP function and indicates that the inhibitor acts by directly blocking the path of the elongating RNA when the transcript becomes 2 to 3 nt in length.
Journal ArticleDOI
Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis
Amalio Telenti,P Imboden,F Marchesi,Lukas Matter,K Schopfer,Thomas Bodmer,Douglas B. Lowrie,M.J Colston,Stewart T. Cole +8 more
TL;DR: Substitution of a limited number of highly conserved aminoacids encoded by the rpoB gene appears to be the molecular mechanism responsible for "single step" high-level resistance to rifampicin in M tuberculosis, a marker of multidrug-resistant tuberculosis.
Journal ArticleDOI
The ATP binding cassette (ABC) transport systems of Mycobacterium tuberculosis
Martine Braibant,Philippe Gilot +1 more
TL;DR: The inventory and assembly of the typical subunits of the ABC transporters encoded by the complete genome of Mycobacterium tuberculosis found that there is an under-representation of the importers in M. tuberculosis, which may reflect the capacity of this bacterium to synthesize many essential compounds and to grow in the presence of few external nutrients.
Journal ArticleDOI
Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis.
TL;DR: The fluctuation test shows that Mycobacterium tuberculosis mutates to resistance to isoniazid, streptomycin, ethambutol and rifampin spontaneously and at random.