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
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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
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Geographical Differences Associated with Single-Nucleotide Polymorphisms (SNPs) in Nine Gene Targets among Resistant Clinical Isolates of Mycobacterium tuberculosis
Matt Hoshide,Lishi Qian,Camilla Rodrigues,Rob Warren,Tommie C. Victor,Henry B. Evasco,Thelma Tupasi,Valeriu Crudu,James T. Douglas +8 more
TL;DR: Differences in polymorphism frequencies emphasize the uniqueness of isolates found in different geographical regions.
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Small Molecule Efflux Pump Inhibitors in Mycobacterium tuberculosis: A Rational Drug Design Perspective
TL;DR: It is shown that, where a direct interaction with efflux pumps is expected, both molecular structure and general physicochemical properties should be considered to accurately predict efflux pump substrates and inhibitors, and it is essential to differentiate between competitive and non-competitive inhibition to accurately determine structure activity relationships for efflux Pump inhibition.
Journal ArticleDOI
Efflux Activity Differentially Modulates the Levels of Isoniazid and Rifampicin Resistance among Multidrug Resistant and Monoresistant Mycobacterium tuberculosis Strains
Diana Machado,João Perdigão,Isabel Portugal,Marco Pieroni,Pedro Almeida da Silva,Isabel Couto,Miguel Viveiros +6 more
TL;DR: It is shown that efflux activity modulates the levels of drug resistance between monoresistant and M/XDR M. tuberculosis clinical strains, allowing the bacteria to survive in the presence of noxious compounds.
Journal ArticleDOI
Translating basic science insight into public health action for multidrug- and extensively drug-resistant tuberculosis.
Nicholas D. Walter,Michael J. Strong,Robert Belknap,Diane J. Ordway,Charles L. Daley,Edward D. Chan,Edward D. Chan +6 more
TL;DR: Progress in understanding Mycobacterium tuberculosis strain‐specific human immune responses, integration of systems biology approaches with traditional epidemiology and insight into the biology of mycobacterial persistence have potential to be translated into new tools for diagnosis and treatment of MDR‐ and XDR‐TB.
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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.
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