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bedaquiline

  • Differential <em>In Vitro</em> Activities of Individual Drugs and Bedaquiline-Rifabutin Combinations against Actively Multiplying and Nutrient-Starved <span class="named-content genus-species" id="named-content-1">Mycobacterium abscessus</span>
    Experimental Therapeutics
    Differential In Vitro Activities of Individual Drugs and Bedaquiline-Rifabutin Combinations against Actively Multiplying and Nutrient-Starved Mycobacterium abscessus

    Current treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net nonreplicating...

    Jin Lee, Nicole Ammerman, Anusha Agarwal, Maram Naji, Si-Yang Li, Eric Nuermberger
  • <em>In Vitro</em> Susceptibility of <span class="named-content genus-species" id="named-content-1">Nocardia farcinica</span> to the Antimycobacterial Drug Clofazimine
    Letter to the Editor
    In Vitro Susceptibility of Nocardia farcinica to the Antimycobacterial Drug Clofazimine
    Ka Lip Chew, Sophie Octavia, Siang Fei Yeoh, Jeanette W. P. Teo
  • Preserved Efficacy and Reduced Toxicity with Intermittent Linezolid Dosing in Combination with Bedaquiline and Pretomanid in a Murine Tuberculosis Model
    Pharmacology
    Preserved Efficacy and Reduced Toxicity with Intermittent Linezolid Dosing in Combination with Bedaquiline and Pretomanid in a Murine Tuberculosis Model

    The novel regimen of bedaquiline, pretomanid, and linezolid (BPaL) is highly effective against drug-resistant tuberculosis, but linezolid toxicities are frequent. We hypothesized that, for a similar total weekly cumulative dose, thrice-weekly administration of linezolid would preserve efficacy while reducing toxicity compared with daily dosing, in the context of the BPaL regimen. Using C3HeB/FeJ and BALB/c mouse models of tuberculosis...

    Kristina M. Bigelow, Rokeya Tasneen, Yong S. Chang, Kelly E. Dooley, Eric L. Nuermberger
  • Toward a Single-Dose Cure for Buruli Ulcer
    Editor's Pick Clinical Therapeutics
    Toward a Single-Dose Cure for Buruli Ulcer

    A single dose of Q203 (Telacebec), a phase 2 clinical candidate for tuberculosis, eradicates Mycobacterium ulcerans in a mouse model of Buruli ulcer infection without relapse up to 19 weeks posttreatment. Clinical use of Q203 may dramatically simplify the clinical management of Buruli ulcer, a neglected mycobacterial disease.

    Sangeeta S. Thomas, Nitin Pal Kalia, Marie-Thérèse Ruf, Gerd Pluschke, Kevin Pethe
  • A Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance Determination
    Clinical Therapeutics
    A Multimethod, Multicountry Evaluation of Breakpoints for Bedaquiline Resistance Determination

    Criteria defining bedaquiline resistance for tuberculosis have been proposed addressing an emerging concern. We evaluated bedaquiline phenotypic drug susceptibility testing (pDST) criteria using drug-resistant tuberculosis clinical isolates tested at five reference laboratories. Isolates were tested at the proposed bedaquiline MGIT960 and 7H11 agar proportion (AP) critical concentrations and also at higher dilutions. The epidemiological...

    Nazir Ahmed Ismail, Akio Aono, Emanuele Borroni, Daniela Maria Cirillo, Christel Desmaretz, Rumina Hasan, Satoshi Mitarai, Sadia Shakoor, Gabriela Torrea, Koné Kaniga, Shaheed V. Omar
  • Advanced Quantification Methods To Improve the 18b Dormancy Model for Assessing the Activity of Tuberculosis Drugs <em>In Vitro</em>
    Clinical Therapeutics
    Advanced Quantification Methods To Improve the 18b Dormancy Model for Assessing the Activity of Tuberculosis Drugs In Vitro

    One of the reasons for the lengthy tuberculosis (TB) treatment is the difficulty to treat the nonmultiplying mycobacterial subpopulation. In order to assess the ability of (new) TB drugs to target this subpopulation, we need to incorporate dormancy models in our preclinical drug development pipeline. In most available dormancy models, it takes a long time to create a dormant state, and it is difficult to identify and quantify this...

    E. D. Pieterman, M. J. Sarink, C. Sala, S. T. Cole, J. E. M. de Steenwinkel, H. I. Bax
  • Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against <span class="named-content genus-species" id="named-content-1">Mycobacterium abscessus</span> in C3HeB/FeJ Mice
    Experimental Therapeutics
    Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against Mycobacterium abscessus in C3HeB/FeJ Mice

    Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics, such as bedaquiline and imipenem, although in vitro data have questioned this combination. We report that the efficacy of bedaquiline-imipenem combination treatment relies essentially on the activity of bedaquiline in...

    Vincent Le Moigne, Clément Raynaud, Flavie Moreau, Christian Dupont, Jérôme Nigou, Olivier Neyrolles, Laurent Kremer, Jean-Louis Herrmann
  • Open Access
    TBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against <span class="named-content genus-species" id="named-content-1">Mycobacterium abscessus</span>
    Experimental Therapeutics
    TBAJ-876, a 3,5-Dialkoxypyridine Analogue of Bedaquiline, Is Active against Mycobacterium abscessus

    Lung disease caused by Mycobacterium abscessus is very difficult to cure, and treatment failure rates are high. The antituberculosis drug bedaquiline (BDQ) is used as salvage therapy against this dreadful disease. However, BDQ is highly lipophilic, displays a long terminal half-life, and presents a cardiotoxicity liability associated with QT interval prolongation....

    Jickky Palmae Sarathy, Uday S. Ganapathy, Matthew D. Zimmerman, Véronique Dartois, Martin Gengenbacher, Thomas Dick
  • Open Access
    TBAJ-876 Displays Bedaquiline-Like Mycobactericidal Potency without Retaining the Parental Drug’s Uncoupler Activity
    Mechanisms of Action: Physiological Effects
    TBAJ-876 Displays Bedaquiline-Like Mycobactericidal Potency without Retaining the Parental Drug’s Uncoupler Activity

    The diarylquinoline F1FO-ATP synthase inhibitor bedaquiline (BDQ) displays protonophore activity. Thus, uncoupling electron transport from ATP synthesis appears to be a second mechanism of action of this antimycobacterial drug. Here, we show that the new BDQ analogue TBAJ-876 did not retain the parental drug’s protonophore activity. Comparative time-kill analyses revealed that both compounds exert the same...

    Jickky Palmae Sarathy, Priya Ragunathan, Christopher B. Cooper, Anna M. Upton, Gerhard Grüber, Thomas Dick
  • Open Access
    TBAJ-876 Retains Bedaquiline’s Activity against Subunits c and ε of <em>Mycobacterium tuberculosis</em> F-ATP Synthase
    Mechanisms of Action: Physiological Effects
    TBAJ-876 Retains Bedaquiline’s Activity against Subunits c and ε of Mycobacterium tuberculosis F-ATP Synthase

    The antituberculosis drug bedaquiline (BDQ) inhibits Mycobacterium tuberculosis F-ATP synthase by interfering with two subunits. Drug binding to the c subunit stalls the rotation of the c ring, while binding to the ε subunit blocks coupling of c ring rotation to ATP synthesis at the catalytic α3:β3 headpiece. BDQ is used for the treatment of drug...

    Jickky Palmae Sarathy, Priya Ragunathan, Joon Shin, Christopher B. Cooper, Anna M. Upton, Gerhard Grüber, Thomas Dick

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