Emerging opportunities of exploiting mycobacterial electron transport chain pathway for drug-resistant tuberculosis drug discovery

References

• WHO. Global tuberculosis report 2018. Geneva, Switzerland: WHO; 2018.
   Google Scholar
• Dartois V. The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells. Nature Rev Microbiol. 2014 Mar;12(3):159–167.
   PubMed Web of Science ®Google Scholar
• Phillips L. Infectious disease: TB’s revenge. Nature. 2013 Jan 3;493(7430):14–16.
   PubMed Web of Science ®Google Scholar
• Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. N Engl J Med. 2008 Aug 7;359(6):563–574.
   PubMed Web of Science ®Google Scholar
• Sacks LV, Behrman RE. Challenges, successes and hopes in the development of novel TB therapeutics. Future Med Chem. 2009 Jul;1(4):749–756.
   PubMed Web of Science ®Google Scholar
• Bald D, Villellas C, Lu P, et al. Targeting Energy Metabolism in Mycobacterium tuberculosis, a New Paradigm in Antimycobacterial Drug Discovery. mBio. 2017 Apr 11;8(2):e00272-17.
   PubMed Web of Science ®Google Scholar
• Horsburgh CR Jr., Barry CE 3rd, Lange C. Treatment of Tuberculosis. N Engl J Med. 2015 Nov 26;373(22):2149–2160.
   PubMed Web of Science ®Google Scholar
• Koul A, Dendouga N, Vergauwen K, et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 2007 Jun;3(6):323–324.
   PubMed Web of Science ®Google Scholar
• Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005 Jan 14;307(5707):223–227.
   PubMed Web of Science ®Google Scholar
• Kundu S, Biukovic G, Gruber G, et al. Bedaquiline Targets the epsilon Subunit of Mycobacterial F-ATP Synthase. Antimicrob Agents Chemother. 2016 Nov;60(11):6977–6979.
   PubMed Web of Science ®Google Scholar
• Joon S, Ragunathan P, Sundararaman L, et al. The NMR solution structure of Mycobacterium tuberculosis F-ATP synthase subunit epsilon provides new insight into energy coupling inside the rotary engine. Febs J. 2018 Mar;285(6):1111–1128.
   PubMed Web of Science ®Google Scholar
• Hards K, McMillan DGG, Schurig-Briccio LA, et al. Ionophoric effects of the antitubercular drug bedaquiline. Proc Natl Acad Sci U S A. 2018 Jul 10;115(28):7326–7331.
   PubMed Web of Science ®Google Scholar
• Pethe K, Bifani P, Jang J, et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med. 2013 Sep;19(9):1157–1160.
   PubMed Web of Science ®Google Scholar
• Gong H, Li J, Xu A, et al. An electron transfer path connects subunits of a mycobacterial respiratory supercomplex. Science. 2018 Nov 30;362(6418):eaat8923.
   Web of Science ®Google Scholar
• Kalia NP, Hasenoehrl EJ, Ab Rahman NB, et al. Exploiting the synthetic lethality between terminal respiratory oxidases to kill Mycobacterium tuberculosis and clear host infection. Proc Natl Acad Sci U S A. 2017 Jul 11;114(28):7426–7431.
   PubMed Web of Science ®Google Scholar
• Lu P, Asseri AH, Kremer M, et al. The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd. Sci Rep. 2018 Feb 8;8(1):2625.
   PubMed Web of Science ®Google Scholar
• Lechartier B, Cole ST. Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2015 Aug;59(8):4457–4463.
   PubMed Web of Science ®Google Scholar
• Yano T, Kassovska-Bratinova S, Teh JS, et al. Reduction of clofazimine by mycobacterial type 2 NADH: quinoneoxidoreductase: a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem. 2011 Mar 25;286(12):10276–10287.
   PubMed Web of Science ®Google Scholar
• Dey T, Brigden G, Cox H, et al. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother. 2013 Feb;68(2):284–293.
   PubMed Web of Science ®Google Scholar
• Mirnejad R, Asadi A, Khoshnood S, et al. Clofazimine: A useful antibiotic for drug-resistant tuberculosis. Biomed Pharmacothe. 2018;105:1353–1359.
   PubMed Web of Science ®Google Scholar
• Rao SP, Alonso S, Rand L, et al. The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11945–11950.
   PubMed Web of Science ®Google Scholar
• Singh P, Rameshwaram NR, Ghosh S, et al. Cell envelope lipids in the pathophysiology of Mycobacterium tuberculosis. Future Microbiol. 2018;13:689–710.
   PubMed Web of Science ®Google Scholar
• Favrot L, Ronning DR. Targeting the mycobacterial envelope for tuberculosis drug development. Expert Rev Anti Infect Ther. 2012 Sep;10(9):1023–1036.
   PubMed Web of Science ®Google Scholar
• Tarcsay A, Keseru GM. Contributions of molecular properties to drug promiscuity. J Med Chem. 2013 Mar 14;56(5):1789–1795.
   PubMed Web of Science ®Google Scholar
• Waring MJ. Lipophilicity in drug discovery. Expert Opin Drug Discov. 2010 Mar;5(3):235–248.
   PubMed Web of Science ®Google Scholar
• O’Shea R, Moser HE. Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem. 2008 May 22;51(10):2871–2878.
   PubMed Web of Science ®Google Scholar
• Koul A, Arnoult E, Lounis N, et al. The challenge of new drug discovery for tuberculosis. Nature. 2011 Jan 27;469(7331):483–490.
   PubMed Web of Science ®Google Scholar
• Lipinski CA, Lombardo F, Dominy BW, et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001 Mar 1;46(1–3):3–26.
   PubMed Web of Science ®Google Scholar
• Manjunatha UH, Smith PW. Perspective: challenges and opportunities in TB drug discovery from phenotypic screening. Bioorg Med Chem. 2015 Aug 15;23(16):5087–5097.
   PubMed Web of Science ®Google Scholar
• Machado D, Girardini M, Viveiros M, et al. Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis. Front Microbiol. 2018;9:1367.
   PubMed Web of Science ®Google Scholar
• Greenwood DJ, Dos Santos MS, Huang S, et al. Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages. Science. 2019 Jun 28;364(6447):1279–1282.
   PubMed Web of Science ®Google Scholar
• Preiss L, Langer JD, Yildiz O, et al. Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline. Sci Adv. 2015 May;1(4):e1500106.
   PubMed Web of Science ®Google Scholar
• Zhang AT, Montgomery MG, Leslie AGW, et al. The structure of the catalytic domain of the ATP synthase from Mycobacterium smegmatis is a target for developing antitubercular drugs. Proceedings of the National Academy of Sciences of the United States of America. 2019 Jan 25;116(10):4206–4211.
   Google Scholar
• Sassetti CM, Boyd DH, Rubin EJ. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol. 2003 Apr;48(1):77–84.
   PubMed Web of Science ®Google Scholar
• Tran SL, Cook GM. The F1Fo-ATP synthase of Mycobacterium smegmatis is essential for growth. J Bacteriol. 2005 Jul;187(14):5023–5028.
   PubMed Web of Science ®Google Scholar
• Cook GM, Hards K, Vilcheze C, et al. Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria. Microbiol Spectr. 2014 Jun;2(3):MGM2-0015-2013.
   Google Scholar
• Cook GM, Hards K, Dunn E, et al. Oxidative Phosphorylation as a Target Space for Tuberculosis: success, Caution, and Future Directions. Microbiol Spectr. 2017 Jun;5(3):TBTB2-0014-2016.
   PubMed Web of Science ®Google Scholar
• Hartman T, Weinrick B, Vilcheze C, et al. Succinate dehydrogenase is the regulator of respiration in Mycobacterium tuberculosis. PLoS Pathog. 2014 Nov;10(11):e1004510.
   PubMed Web of Science ®Google Scholar
• Pecsi I, Hards K, Ekanayaka N, et al. Essentiality of succinate dehydrogenase in Mycobacterium smegmatis and its role in the generation of the membrane potential under hypoxia. mBio. 2014 Aug 12;5(4):e01093-14.
   PubMed Web of Science ®Google Scholar
• Watanabe S, Zimmermann M, Goodwin MB, et al. Fumarate reductase activity maintains an energized membrane in anaerobic Mycobacterium tuberculosis. PLoS Pathog. 2011 Oct;7(10):e1002287.
   PubMed Web of Science ®Google Scholar
• Feng X, Zhu W, Schurig-Briccio LA, et al. Antiinfectives targeting enzymes and the proton motive force. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):E7073–82.
   PubMed Web of Science ®Google Scholar
• Bald D, Koul A. Respiratory ATP synthesis: the new generation of mycobacterial drug targets? FEMS Microbiol Lett. 2010 Jul 1;308(1):1–7.
   PubMed Web of Science ®Google Scholar
• Boyer PD. The ATP synthase–a splendid molecular machine. Annu Rev Biochem. 1997;66:717–749.
   PubMed Web of Science ®Google Scholar
• Pogoryelov D, Krah A, Langer JD, et al. Microscopic rotary mechanism of ion translocation in the F(o) complex of ATP synthases. Nat Chem Biol. 2010 Dec;6(12):891–899.
   PubMed Web of Science ®Google Scholar
• Hakulinen JK, Klyszejko AL, Hoffmann J, et al. Structural study on the architecture of the bacterial ATP synthase Fo motor. Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):E2050–6.
   PubMed Web of Science ®Google Scholar
• Pogoryelov D, Yildiz O, Faraldo-Gomez JD, et al. High-resolution structure of the rotor ring of a proton-dependent ATP synthase. Nat Struct Mol Biol. 2009 Oct;16(10):1068–1073.
   PubMed Web of Science ®Google Scholar
• Segala E, Sougakoff W, Nevejans-Chauffour A, et al. New mutations in the mycobacterial ATP synthase: new insights into the binding of the diarylquinoline TMC207 to the ATP synthase C-ring structure. Antimicrob Agents Chemother. 2012 May;56(5):2326–2334.
   PubMed Web of Science ®Google Scholar
• Petrella S, Cambau E, Chauffour A, et al. Genetic basis for natural and acquired resistance to the diarylquinoline R207910 in mycobacteria. Antimicrob Agents Chemother. 2006 Aug;50(8):2853–2856.
   PubMed Web of Science ®Google Scholar
• Huitric E, Verhasselt P, Koul A, et al. Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2010 Mar;54(3):1022–1028.
   PubMed Web of Science ®Google Scholar
• Bown L, Srivastava SK, Piercey BM, et al. Mycobacterial membrane proteins QcrB and AtpE: roles in energetics, antibiotic targets, and associated mechanisms of resistance. J Membr Biol. 2018 Feb;251(1):105–117.
   PubMed Web of Science ®Google Scholar
• Tantry SJ, Markad SD, Shinde V, et al. Discovery of Imidazo[1,2-a]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis. J Med Chem. 2017 Feb 23;60(4):1379–1399.
   PubMed Web of Science ®Google Scholar
• Singh S, Roy KK, Khan SR, et al. Novel, potent, orally bioavailable and selective mycobacterial ATP synthase inhibitors that demonstrated activity against both replicating and non-replicating M. tuberculosis. Bioorg Med Chem. 2015 Feb 15;23(4):742–752.
   PubMed Web of Science ®Google Scholar
• Lu P, Heineke MH, Koul A, et al. The cytochrome bd-type quinol oxidase is important for survival of Mycobacterium smegmatis under peroxide and antibiotic-induced stress. Sci Rep. 2015 May 27;5:10333.
   PubMed Web of Science ®Google Scholar
• Abrahams KA, Cox JA, Spivey VL, et al. Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB. PloS One. 2012;7(12):e52951.
   PubMed Web of Science ®Google Scholar
• Moraski GC, Markley LD, Hipskind PA, et al. Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis Activity. ACS Med Chem Lett. 2011 Jun 9;2(6):466–470.
   PubMed Web of Science ®Google Scholar
• Lu X, Williams Z, Hards K, et al. Pyrazolo[1,5- a]pyridine Inhibitor of the Respiratory Cytochrome bcc Complex for the Treatment of Drug-Resistant Tuberculosis. ACS Infect Dis. 2019 Feb 8;5(2):239–249.
   PubMed Web of Science ®Google Scholar
• van der Westhuyzen R, Winks S, Wilson CR, et al. Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration. J Med Chem. 2015 Dec 10;58(23):9371–9381.
   PubMed Web of Science ®Google Scholar
• Foo CS, Lupien A, Kienle M, et al. Arylvinylpiperazine Amides, a New Class of Potent Inhibitors Targeting QcrB of Mycobacterium tuberculosis. mBio. 2018 Oct 9;9(5):e01276-18.
   PubMed Web of Science ®Google Scholar
• Iqbal IK, Bajeli S, Akela AK, et al. Bioenergetics of Mycobacterium: an Emerging Landscape for Drug Discovery. Pathogens. 2018 Feb 23;7(1):E24.
   PubMed Web of Science ®Google Scholar
• Teh JS, Yano T, Rubin H. Type II NADH: menaquinone oxidoreductase of Mycobacterium tuberculosis. Infect Disord Drug Targets. 2007 Jun;7(2):169–181.
   PubMedGoogle Scholar
• Gadre DV, Talwar V, Gupta HC, et al. Effect of trifluoperazine, a potential drug for tuberculosis with psychotic disorders, on the growth of clinical isolates of drug resistant Mycobacterium tuberculosis. Int Clin Psychopharmacol. 1998 May;13(3):129–131.
   PubMed Web of Science ®Google Scholar
• Lamprecht DA, Finin PM, Rahman MA, et al. Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. Nat Commun. 2016 Aug 10;7:12393.
   PubMed Web of Science ®Google Scholar
• Tyagi S, Ammerman NC, Li SY, et al. Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis. Proc Natl Acad Sci U S A. 2015 Jan 20;112(3):869–874.
   PubMed Web of Science ®Google Scholar
• Ochoa-Montano B, Mohan N, Blundell TL. CHOPIN: a web resource for the structural and functional proteome of Mycobacterium tuberculosis. Database. 2015 March 31;2015:bav026.
   Google Scholar
• Skwark MJ, Torres PHM, Copoiu L, et al. Mabellini: a genome-wide database for understanding the structural proteome and evaluating prospective antimicrobial targets of the emerging pathogen Mycobacterium abscessus. Database. 2019 Jan 1;2019:baz113.
   PubMedGoogle Scholar
• Small JL, Park SW, Kana BD, et al. Perturbation of cytochrome c maturation reveals adaptability of the respiratory chain in Mycobacterium tuberculosis. mBio. 2013 Sep 17;4(5):e00475–13.
   PubMed Web of Science ®Google Scholar
• Kana BD, Weinstein EA, Avarbock D, et al. Characterization of the cydAB-encoded cytochrome bd oxidase from Mycobacterium smegmatis. J Bacteriol. 2001 Dec;183(24):7076–7086.
   PubMed Web of Science ®Google Scholar
• Koul A, Vranckx L, Dhar N, et al. Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism. Nat Commun. 2014 Feb;26(5):3369.
   Web of Science ®Google Scholar
• Berney M, Hartman TE, Jacobs WR Jr. A Mycobacterium tuberculosis cytochrome bd oxidase mutant is hypersensitive to bedaquiline. mBio. 2014 Jul 15;5(4):e01275–14.
   PubMed Web of Science ®Google Scholar
• Safarian S, Rajendran C, Muller H, et al. Structure of a bd oxidase indicates similar mechanisms for membrane-integrated oxygen reductases. Science. 2016 Apr 29;352(6285):583–586.
   PubMed Web of Science ®Google Scholar
• Haagsma AC, Abdillahi-Ibrahim R, Wagner MJ, et al. Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue. Antimicrob Agents Chemother. 2009 Mar;53(3):1290–1292.
   PubMed Web of Science ®Google Scholar
• Fiorillo M, Lamb R, Tanowitz HB, et al. Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs). Aging (Albany NY). 2016 8;Aug(8):1593–1607.
   Google Scholar
• de Miranda Silva C, Hajihosseini A, Myrick J, et al. Effect of Linezolid plus Bedaquiline against Mycobacterium tuberculosis in Log Phase, Acid Phase, and Nonreplicating-Persister Phase in an In Vitro Assay. Antimicrob Agents Chemother. 2018 Aug;62(8):e00856-18.
   PubMed Web of Science ®Google Scholar
• Abutaleb Y. New antibiotic approved for drug-resistant tuberculosis Washington: Washington Post; 2019 [cited 2019 Aug 14]; https://www.washingtonpost.com/health/new-antibiotic-approved-for-drug-resistant-tuberculosis/2019/08/14/559d069a-bde6-11e9-9b73-fd3c65ef8f9c_story.html?noredirect=on
   Google Scholar
• da Silva PE, Von Groll A, Martin A, et al. Efflux as a mechanism for drug resistance in Mycobacterium tuberculosis. FEMS Immunol Med Microbiol. 2011 Oct;63(1):1–9.
   PubMedGoogle Scholar
• Jang J, Kim R, Woo M, et al. Efflux Attenuates the Antibacterial Activity of Q203 in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2017 Jul;61(7):e02637-16.
   Web of Science ®Google Scholar
• Scherr N, Bieri R, Thomas SS, et al. Targeting the Mycobacterium ulcerans cytochrome bc1: aa3for the treatment of Buruli ulcer. Nat Commun. 2018 Dec 18;9(1):5370.
   PubMed Web of Science ®Google Scholar
• Rybniker J, Vocat A, Sala C, et al. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1. Nat Commun. 2015 Jul 9;6:7659.
   PubMed Web of Science ®Google Scholar
• Pontali E, Sotgiu G, Tiberi S, et al. Cardiac safety of bedaquiline: a systematic and critical analysis of the evidence. Eur Respir J. 2017 Nov;50(5):1701462.
   PubMed Web of Science ®Google Scholar
• Tadolini M, Lingtsang RD, Tiberi S, et al. Cardiac safety of extensively drug-resistant tuberculosis regimens including bedaquiline, delamanid and clofazimine. Eur Respir J. 2016 Nov;48(5):1527–1529.
   PubMed Web of Science ®Google Scholar
• Wallis RS. Cardiac safety of extensively drug-resistant tuberculosis regimens including bedaquiline, delamanid and clofazimine. Eur Respir J. 2016 Nov;48(5):1526–1527.
   PubMed Web of Science ®Google Scholar
• Gupta S, Cohen KA, Winglee K, et al. Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014;58(1):574–576.
   PubMed Web of Science ®Google Scholar
• Pule CM, Sampson SL, Warren RM, et al. Efflux pump inhibitors: targeting mycobacterial efflux systems to enhance TB therapy. J Antimicrob Chemother. 2016 Jan;71(1):17–26.
   PubMed Web of Science ®Google Scholar
• Gupta S, Tyagi S, Almeida DV, et al. Acceleration of tuberculosis treatment by adjunctive therapy with verapamil as an efflux inhibitor. Am J Respir Crit Care Med. 2013 Sep 1;188(5):600–607.
   PubMed Web of Science ®Google Scholar