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  1. Article ; Online: Turning the respiratory flexibility of Mycobacterium tuberculosis against itself.

    Lamprecht, Dirk A / Finin, Peter M / Rahman, Md Aejazur / Cumming, Bridgette M / Russell, Shannon L / Jonnala, Surendranadha R / Adamson, John H / Steyn, Adrie J C

    Nature communications

    2016  Volume 7, Page(s) 12393

    Abstract: The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by its flexibility in response to disruption. Here we determine the effect of the ETC ... ...

    Abstract The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by its flexibility in response to disruption. Here we determine the effect of the ETC inhibitors bedaquiline, Q203 and clofazimine on the Mtb ETC, and the value of the ETC as a drug target, by measuring Mtb's respiration using extracellular flux technology. We find that Mtb's ETC rapidly reroutes around inhibition by these drugs and increases total respiration to maintain ATP levels. Rerouting is possible because Mtb rapidly switches between terminal oxidases, and, unlike eukaryotes, is not susceptible to back pressure. Increased ETC activity potentiates clofazimine's production of reactive oxygen species, causing rapid killing in vitro and in a macrophage model. Our results indicate that combination therapy targeting the ETC can be exploited to enhance killing of Mtb.
    MeSH term(s) Adenosine Triphosphate/metabolism ; Animals ; Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Clofazimine/pharmacology ; Clofazimine/therapeutic use ; Diarylquinolines/pharmacology ; Diarylquinolines/therapeutic use ; Drug Therapy, Combination/methods ; Electron Transport Chain Complex Proteins/antagonists & inhibitors ; Hep G2 Cells ; Humans ; Imidazoles/chemical synthesis ; Imidazoles/pharmacology ; Imidazoles/therapeutic use ; Inhibitory Concentration 50 ; Macrophages/microbiology ; Mice ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/physiology ; Piperidines/chemical synthesis ; Piperidines/pharmacology ; Piperidines/therapeutic use ; Pyridines/chemical synthesis ; Pyridines/pharmacology ; Pyridines/therapeutic use ; RAW 264.7 Cells ; Reactive Oxygen Species/metabolism ; Tuberculosis, Multidrug-Resistant/drug therapy ; Tuberculosis, Multidrug-Resistant/microbiology
    Chemical Substances Antitubercular Agents ; Diarylquinolines ; Electron Transport Chain Complex Proteins ; Imidazoles ; Piperidines ; Pyridines ; Reactive Oxygen Species ; telacebec (55G92WGH3X) ; bedaquiline (78846I289Y) ; Adenosine Triphosphate (8L70Q75FXE) ; Clofazimine (D959AE5USF)
    Language English
    Publishing date 2016-08-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/ncomms12393
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: 2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization.

    Murugesan, Dinakaran / Ray, Peter C / Bayliss, Tracy / Prosser, Gareth A / Harrison, Justin R / Green, Kirsteen / Soares de Melo, Candice / Feng, Tzu-Shean / Street, Leslie J / Chibale, Kelly / Warner, Digby F / Mizrahi, Valerie / Epemolu, Ola / Scullion, Paul / Ellis, Lucy / Riley, Jennifer / Shishikura, Yoko / Ferguson, Liam / Osuna-Cabello, Maria /
    Read, Kevin D / Green, Simon R / Lamprecht, Dirk A / Finin, Peter M / Steyn, Adrie J C / Ioerger, Thomas R / Sacchettini, Jim / Rhee, Kyu Y / Arora, Kriti / Barry, Clifton E / Wyatt, Paul G / Boshoff, Helena I M

    ACS infectious diseases

    2018  Volume 4, Issue 6, Page(s) 954–969

    Abstract: Mycobacterium tuberculosis ( MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been ... ...

    Abstract Mycobacterium tuberculosis ( MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.
    MeSH term(s) Molecular Structure ; Mycobacterium tuberculosis/enzymology ; NADH Dehydrogenase/antagonists & inhibitors ; NADH Dehydrogenase/chemistry ; Quinazolinones/chemical synthesis ; Quinazolinones/chemistry ; Quinazolinones/pharmacology ; Structure-Activity Relationship
    Chemical Substances Quinazolinones ; NADH dehydrogenase II (EC 1.6.99.-) ; NADH Dehydrogenase (EC 1.6.99.3)
    Language English
    Publishing date 2018-03-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2373-8227
    ISSN (online) 2373-8227
    DOI 10.1021/acsinfecdis.7b00275
    Database MEDical Literature Analysis and Retrieval System OnLINE

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