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Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions

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  • Authors: Gregory M. Cook1, Kiel Hards3, Elyse Dunn4, Adam Heikal5, Yoshio Nakatani7, Chris Greening9, Dean C. Crick11, Fabio L. Fontes12, Kevin Pethe13, Erik Hasenoehrl14, Michael Berney15
  • Editors: William R. Jacobs Jr.16, Helen McShane17, Valerie Mizrahi18, Ian M. Orme19
    Affiliations: 1: University of Otago, Department of Microbiology and Immunology, Otago School of Medical Sciences, Dunedin, New Zealand; 2: Maurice Wilkins Center for Molecular Biodiscovery, The University of Auckland, Auckland 1042, New Zealand; 3: University of Otago, Department of Microbiology and Immunology, Otago School of Medical Sciences, Dunedin, New Zealand; 4: University of Otago, Department of Microbiology and Immunology, Otago School of Medical Sciences, Dunedin, New Zealand; 5: University of Otago, Department of Microbiology and Immunology, Otago School of Medical Sciences, Dunedin, New Zealand; 6: Maurice Wilkins Center for Molecular Biodiscovery, The University of Auckland, Auckland 1042, New Zealand; 7: University of Otago, Department of Microbiology and Immunology, Otago School of Medical Sciences, Dunedin, New Zealand; 8: Maurice Wilkins Center for Molecular Biodiscovery, The University of Auckland, Auckland 1042, New Zealand; 9: The Commonwealth Scientific and Industrial Research Organization, Land and Water Flagship, Acton ACT, Australia; 10: Monash University, School of Biological Sciences, Clayton VIC, Australia; 11: Colorado State University, Department of Microbiology, Immunology, and Pathology, Fort Collins, CO 80523; 12: Colorado State University, Department of Microbiology, Immunology, and Pathology, Fort Collins, CO 80523; 13: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 14: Albert Einstein School of Medicine, Department of Microbiology and Immunology, Bronx, NY 10461; 15: Albert Einstein School of Medicine, Department of Microbiology and Immunology, Bronx, NY 10461; 16: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 17: University of Oxford, Oxford OX3 7DQ, United Kingdom; 18: University of Cape Town, Rondebosch 7701, South Africa; 19: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0014-2016
  • Received 09 February 2016 Accepted 31 March 2017 Published 09 June 2017
  • Greg Cook, [email protected]
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  • Abstract:

    The emergence and spread of drug-resistant pathogens, and our inability to develop new antimicrobials to combat resistance, have inspired scientists to seek out new targets for drug development. The complex is a group of obligately aerobic bacteria that have specialized for inhabiting a wide range of intracellular and extracellular environments. Two fundamental features in this adaptation are the flexible utilization of energy sources and continued metabolism in the absence of growth. is an obligately aerobic heterotroph that depends on oxidative phosphorylation for growth and survival. However, several studies are redefining the metabolic breadth of the genus. Alternative electron donors and acceptors may provide the maintenance energy for the pathogen to maintain viability in hypoxic, nonreplicating states relevant to latent infection. This hidden metabolic flexibility may ultimately decrease the efficacy of drugs targeted against primary dehydrogenases and terminal oxidases. However, it may also open up opportunities to develop novel antimycobacterials targeting persister cells. In this review, we discuss the progress in understanding the role of energetic targets in mycobacterial physiology and pathogenesis and the opportunities for drug discovery.

  • Citation: Cook G, Hards K, Dunn E, Heikal A, Nakatani Y, Greening C, Crick D, Fontes F, Pethe K, Hasenoehrl E, Berney M. 2017. Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions. Microbiol Spectrum 5(3):TBTB2-0014-2016. doi:10.1128/microbiolspec.TBTB2-0014-2016.


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The emergence and spread of drug-resistant pathogens, and our inability to develop new antimicrobials to combat resistance, have inspired scientists to seek out new targets for drug development. The complex is a group of obligately aerobic bacteria that have specialized for inhabiting a wide range of intracellular and extracellular environments. Two fundamental features in this adaptation are the flexible utilization of energy sources and continued metabolism in the absence of growth. is an obligately aerobic heterotroph that depends on oxidative phosphorylation for growth and survival. However, several studies are redefining the metabolic breadth of the genus. Alternative electron donors and acceptors may provide the maintenance energy for the pathogen to maintain viability in hypoxic, nonreplicating states relevant to latent infection. This hidden metabolic flexibility may ultimately decrease the efficacy of drugs targeted against primary dehydrogenases and terminal oxidases. However, it may also open up opportunities to develop novel antimycobacterials targeting persister cells. In this review, we discuss the progress in understanding the role of energetic targets in mycobacterial physiology and pathogenesis and the opportunities for drug discovery.

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Image of FIGURE 1

Generalized schematic overview of relevant electron transfer components of . Complexes indicated in blue oxidize various substrates to reduce quinones. The resulting (mena)quinol molecules (orange) can be oxidized to result in reduction of various terminal electron acceptors, mediated by the complexes shown in purple.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0014-2016
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Mechanisms by which a proton motive (membrane potential [Δψ] + transmembrane pH gradient [ZΔpH]) force can be generated in mycobacteria. Cotransport of protons driven by solute (succinate) symport into the periplasm. Redox-loop separation of charge; (mena)quinol oxidation results in proton release into the periplasm by virtue of (mena)quinol site proximity to the periplasm, while electrons are transferred to reduce a terminal electron acceptor (e.g., nitrate, fumarate) in the cytoplasm that results in neutralization of charge. Proton translocation mediated by primary proton-pumping complexes ( - supercomplex).

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0014-2016
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Traditional inhibitors of proton motive force generation. Valinomycin is an ionophore, selective for potassium ions, which equilibrates the potassium gradient—dissipating the Δψ (electrogenic). Nigericin is a hydrophobic weak carboxylic acid which can traverse the membrane as its either protonated acid or neutral salt. It dissipates chemical gradients (i.e., ΔpH) but maintains the charge (one positive charge exchanged for one positive charge—electroneutral) ( 3 ). Carbonyl cyanide m-chlorophenyl hydrazine (CCCP) is an electrogenic protonophore. CCCP is driven to the periplasm by the Δψ, while CCCPH is driven to the cytoplasm by the ΔpH. It can equilibrate both Δψ and ΔpH. Model for uncoupling by either pyrazinamide (PZA) or BDQ. (Left side) PZA diffuses into the cell and is converted to pyrazinoic acid (POA) by PncA (pyrazinamidase). Anionic POA could effectively inhibit growth through anion accumulation in the neutral pH of the cytoplasm and/or efflux from the cells to become protonated in the acidic extracellular environment (POA-H). POA-H would then diffuse back into the cell driven by the ΔpH gradient and dissociate in the cytoplasm (neutral pH), leading to intracellular acidification and cell death. (Right side) In a typical mycobacterial cell, the majority of ATP synthesis is respiratory, driven by the PMF. The binding of BDQ to the c-ring most likely perturbs the a-c subunit interface, causing an uncontrolled proton leak uncoupled from ATP synthesis and resulting in a futile proton cycle. Compensation by the exchange of other cations (i.e., K) would allow the process to remain electroneutral.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0014-2016
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Inhibitors of the electron transport chain and FF-ATP synthase of . Selected inhibitors of these complexes are indicated with flathead arrows and do not reflect the binding site of the inhibitors. Abbreviations: QPs, quinolinyl pyrimidines; TPZ, trifluoperazine; CFZ, clofazimine; 3-NP, 3-nitropropionate; SQ109, -adamantan-2-yl--(()-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine; LPZ, lansoprazole; Q203, imidazopyridine amide; BDQ, bedaquiline.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0014-2016
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Proposed menaquinone biosynthesis pathway in mycobacteria based on the known pathway in . In this scheme the product of MenA is depicted as the quinone rather than the quinol. This is consistent with the majority of the menaquinone literature ( 167 ), which indicates that the oxidation from quinol to quinone is spontaneous but differs from ubiquinone synthesis. The arrows indicate C2 and C3 of menaquinone-9(II-H). Abbreviations: DHNA, 1,4-dihydroxy-2-naphthoate; DHNA-CoA, 1,4-dihydroxy-2-naphthoyl-CoA; OSB, -succinylbenzoate; OSB-CoA, -succinylbenzoyl-CoA; SEPHCHC, 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate; SHCHC, 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate.

Source: microbiolspec June 2017 vol. 5 no. 3 doi:10.1128/microbiolspec.TBTB2-0014-2016
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