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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Assessment of antibiotic resistance in Klebsiella pneumoniae exposed to sequential in vitro antibiotic treatments.
TL;DR: The results suggest that the pre-exposed antibiotic history, treatment order, and concentrations influenced the development of multiple antibiotic resistant associated with β-lactamase and efflux pump activities.
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Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model
Claire M. Naftalin,Rupangi Verma,Meera Gurumurthy,Kim Hor Hee,Qingshu Lu,Benjamin Chaik Meng Yeo,Kin Hup Tan,Wenwei Lin,Buduo Yu,Kok Yong Seng,Lawrence S. Lee,Nicholas I. Paton +11 more
TL;DR: The lack of benefit of celecoxib suggests that efflux pump inhibition or eicosanoid pathway-related responses are of limited importance in mycobacterial killing in the WBA assay.
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Elsa Du Bruyn,Kiyoshi F. Fukutani,Neesha Rockwood,Neesha Rockwood,Neesha Rockwood,Charlotte Schutz,Graeme Meintjes,María B. Arriaga,Juan M. Cubillos-Angulo,Rafael Tibúrcio,Alan Sher,Catherine Riou,Katalin A. Wilkinson,Katalin A. Wilkinson,Bruno B. Andrade,Robert J. Wilkinson +15 more
TL;DR: The findings show the effect of HIV-1 co-infection on the complexity of plasma inflammatory profiles in patients with tuberculosis, and Interleukin (IL)-17A emerged as a key correlate of AIDS-1-induced inflammation during HIV–tuberculosis co- Infection.
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Wild-type MIC distributions must be considered to set clinically meaningful susceptibility testing breakpoints for all bacterial pathogens, including Mycobacterium tuberculosis.
Kristian Ängeby,Christian G. Giske,Pontus Juréen,Thomas B. Schön,Jotam G. Pasipanodya,Tawando Gumbo +5 more
TL;DR: The authors believe that setting susceptibility breakpoints solely using PK/PD data, without considering wild-type MIC distributions and clinical outcome data if available, could lead to susceptibility reporting with considerable problems in clinical interpretation and reproducibility.
Evaluation of Different Mycobacterial Species for Drug Discovery and Characterisation of Novel Inhibitors of Mycobacterium Tuberculosis
TL;DR: The main objectives of this study were to identify an appropriate in vitro model that could be used for anti-Tuberculosis drug high-throughput screening (HTS), and to use this model to identify a novel candidate anti-tubercular drug and its cognate cellular target.
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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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