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tuberculosis

  • Systematic Review of Mutations Associated with Isoniazid Resistance Points to Continuing Evolution and Subsequent Evasion of Molecular Detection, and Potential for Emergence of Multidrug Resistance in Clinical Strains of <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span>
    Mechanisms of Resistance
    Systematic Review of Mutations Associated with Isoniazid Resistance Points to Continuing Evolution and Subsequent Evasion of Molecular Detection, and Potential for Emergence of Multidrug Resistance in Clinical Strains of Mycobacterium tuberculosis

    Molecular testing is rapidly becoming an integral component of global tuberculosis (TB) control. Uncommon mechanisms of resistance escape detection by these platforms and undermine our ability to contain outbreaks.

    Siavash J. Valafar
  • Replacement of S14 Protein in Ribosomes of Zinc-Starved Mycobacteria Reduces Spectinamide Sensitivity
    Mechanisms of Resistance
    Replacement of S14 Protein in Ribosomes of Zinc-Starved Mycobacteria Reduces Spectinamide Sensitivity

    Zinc is an essential micronutrient for mycobacteria, and its depletion induces multiple adaptive changes in cellular physiology, the most remarkable of which are remodeling and hibernation of ribosomes. Ribosome remodeling, induced upon relatively moderate depletion of zinc, involves replacement of multiple ribosomal proteins containing the zinc-binding CXXC motif (called C+ r proteins) by their motif-free C− paralogs.

    ...
    Yunlong Li, Ravi K. Koripella, Manjuli R. Sharma, Richard E. Lee, Rajendra K. Agrawal, Anil K. Ojha
  • Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis
    Pharmacology
    Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis

    Shorter, more potent regimens are needed for tuberculosis. The nitroimidazole pretomanid was recently approved for extensively drug-resistant tuberculosis in combination with bedaquiline and linezolid.

    Elisa H. Ignatius, Mahmoud Tareq Abdelwahab, Bronwyn Hendricks, Nikhil Gupte, Kim Narunsky, Lubbe Wiesner, Grace Barnes, Rodney Dawson, Kelly E. Dooley, Paolo Denti
    and on behalf of the Assessing Pretomanid for Tuberculosis Study Team
  • Mutations in <em>fbiD</em> (<em>Rv2983</em>) as a Novel Determinant of Resistance to Pretomanid and Delamanid in <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span>
    Editor's Pick Mechanisms of Resistance
    Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

    The nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant...

    Dalin Rifat, Si-Yang Li, Thomas Ioerger, Keshav Shah, Jean-Philippe Lanoix, Jin Lee, Ghader Bashiri, James Sacchettini, Eric Nuermberger
  • Lack of Specificity of Phenotypic Screens for Inhibitors of the <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span> FAS-II System
    Mechanisms of Action: Physiological Effects
    Lack of Specificity of Phenotypic Screens for Inhibitors of the Mycobacterium tuberculosis FAS-II System

    Phenotypic screening of inhibitors of the essential Mycobacterium tuberculosis FAS-II dehydratase HadAB led to the identification of GSK3011724A, a compound previously reported to inhibit the condensation step of FAS-II. Whole-cell-based and cell-free assays confirmed the lack of activity of GSK3011724A against the dehydratase despite evidence of cross-resistance...

    Anna E. Grzegorzewicz, Joël Lelièvre, Jorge Esquivias, Bhanupriya Angala, Jiuyu Liu, Richard E. Lee, Michael R. McNeil, Mary Jackson
  • Treatment Outcomes and Adverse Drug Effects of Ethambutol, Cycloserine, and Terizidone for the Treatment of Multidrug-Resistant Tuberculosis in South Africa
    Clinical Therapeutics
    Treatment Outcomes and Adverse Drug Effects of Ethambutol, Cycloserine, and Terizidone for the Treatment of Multidrug-Resistant Tuberculosis in South Africa

    Treatment outcomes among multidrug-resistant tuberculosis (MDR-TB) patients receiving ethambutol, cycloserine, or terizidone as part of a standardized regimen were compared, determining occurrence of serious adverse drug events (SADEs). Newly diagnosed adult MDR-TB patients were enrolled between 2000 and 2004, receiving a standardized multidrug regimen for 18 to 24 months, including ethambutol, cycloserine, or terizidone. Cycloserine...

    Martha L. van der Walt, Karen Shean, Piet Becker, Karen H. Keddy, Joey Lancaster
  • Disparate Effects of Metformin on <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span> Infection in Diabetic and Nondiabetic Mice
    Experimental Therapeutics
    Disparate Effects of Metformin on Mycobacterium tuberculosis Infection in Diabetic and Nondiabetic Mice

    Comorbid type 2 diabetes poses a great challenge to the global control of tuberculosis. Here, we assessed the efficacy of metformin (MET), an antidiabetic drug, in mice infected with a very low dose of Mycobacterium tuberculosis. In contrast to diabetic mice, infected nondiabetic mice that received the same therapeutic concentration of MET presented with significantly...

    Harindra D. Sathkumara, Karyna Hansen, Socorro Miranda-Hernandez, Brenda Govan, Catherine M. Rush, Lars Henning, Natkunam Ketheesan, Andreas Kupz
  • Open Access
    An Exposure-Response Perspective on the Clinical Dose of Pretomanid
    Clinical Therapeutics
    An Exposure-Response Perspective on the Clinical Dose of Pretomanid

    Pretomanid was approved by the U.S. FDA, via the limited population pathway for antibacterial and antifungal drugs, as part of a three-drug regimen with bedaquiline and linezolid for the treatment of extensively drug-resistant and treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. The recommended dose of pretomanid is 200 mg once daily with food. The objective of this work was to retrospectively evaluate this...

    Jerry R. Nedelman, David H. Salinger, Vishak Subramoney, Rob Woolson, Karen Wade, Mengchun Li, Daniel Everitt, Carl M. Mendel, Mel Spigelman
  • The Unique C-Terminal Extension of Mycobacterial F-ATP Synthase Subunit α Is the Major Contributor to Its Latent ATP Hydrolysis Activity
    Mechanisms of Action: Physiological Effects
    The Unique C-Terminal Extension of Mycobacterial F-ATP Synthase Subunit α Is the Major Contributor to Its Latent ATP Hydrolysis Activity

    Mycobacterial F1Fo-ATP synthases (α3:β3:γ:δ:ε:a:b:b′:c9) are incapable of ATP-driven proton translocation due to their latent ATPase activity. This prevents wasting of ATP and altering of the proton motive force, whose dissipation is lethal to mycobacteria. We demonstrate that the mycobacterial C-terminal extension of nucleotide-binding subunit α...

    Chui-Fann Wong, Gerhard Grüber
  • Amphotericin B Inhibits <span class="named-content genus-species" id="named-content-1">Mycobacterium tuberculosis</span> Infection of Human Alveolar Type II Epithelial A549 Cells
    Letter to the Editor
    Amphotericin B Inhibits Mycobacterium tuberculosis Infection of Human Alveolar Type II Epithelial A549 Cells
    Sabrina Mariotti, Raffaela Teloni, Valeria de Turris, Manuela Pardini, Daniela Peruzzu, Katia Fecchi, Roberto Nisini, Maria Cristina Gagliardi

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