Type-II NADH Dehydrogenase (NDH-2): a promising therapeutic target for antitubercular and antibacterial drug discovery

Expert Opinion on Therapeutic Targets

Volumn 21, Issue 6, 2017, Pages 559-570

  Sellamuthu, Satheeshkumar ^a   Singh, Meenakshi ^a   Kumar, Ashok ^a   Singh, Sushil Kumar ^a  

^a BANARAS HINDU UNIVERSITY   (India)

Author keywords

ATP synthesis; dormant TB; enzyme kinetics; NDH 2; resistant TB; type 2 NADH dehydrogenase

Indexed keywords

ADENOSINE TRIPHOSPHATE; ANTIINFECTIVE AGENT; PHENOTHIAZINE DERIVATIVE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE; TUBERCULOSTATIC AGENT; NADH DEHYDROGENASE II;

CRYSTAL STRUCTURE; DRUG POTENCY; DRUG TARGETING; ENERGY TRANSFER; ENZYME KINETICS; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; REVIEW; STRUCTURE ACTIVITY RELATION; SYNTHESIS; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG DESIGN; DRUG DEVELOPMENT; DRUG EFFECTS; DRUG RESISTANCE; HUMAN; METABOLISM; MICROBIOLOGY; MOLECULARLY TARGETED THERAPY; TUBERCULOSIS;

ANIMALS; ANTI-BACTERIAL AGENTS; ANTITUBERCULAR AGENTS; DRUG DESIGN; DRUG DISCOVERY; DRUG RESISTANCE, NEOPLASM; HUMANS; MOLECULAR TARGETED THERAPY; MYCOBACTERIUM TUBERCULOSIS; NADH DEHYDROGENASE; PHENOTHIAZINES; TUBERCULOSIS;

EID: 85019552967     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1080/14728222.2017.1327577     Document Type: Review

References (87)

1. Chukwuanukwu RC, Onyenekwe CC, Martinez-Pomares L, et al. Modulation of the immune response to Mycobacterium tuberculosis during malaria/M. tuberculosis co-infection. Clin Exp Immunol. 2017;187:259–268.
2. Shiffman J., Four challenges that global health networks face. Int J Health Policy Manag. 2017;6:183–189.
3. Riccardi G, Old IG, Ekins S. Raising awareness of the importance of funding for tuberculosis small-molecule research. Drug Discovery Today. 2017;22:487–491.
4. Organization WH. Global tuberculosis report 2016. 2016.
5. Knechel NA. Tuberculosis:pathophysiology, clinical features, and diagnosis. Crit Care Nurse. 2009;29:34–43.
6. Lin PL, Flynn JL. Understanding latent tuberculosis:a moving target. J Immunol. 2010;185:15–22.
7. Dai R, Wilson DJ, Geders TW, et al. Inhibition of Mycobacterium tuberculosis transaminase BioA by aryl hydrazines and hydrazides. ChemBioChem. 2014;15:575–586.
8. Blair HA, Scott LJ. Delamanid:a review of its use in patients with multidrug-resistant tuberculosis. Drugs. 2015;75:91–100.
9. Lu X, Smare C, Kambili C, et al. Health outcomes of bedaquiline in the treatment of multidrug-resistant tuberculosis in selected high burden countries. BMC Health Serv Res. 2017;17:87.
10. Somoskovi A, Bruderer V, Hömke R, et al. A mutation associated with clofazimine and bedaquiline cross-resistance in MDR-TB following bedaquiline treatment. Eur Respir J. 2015;45(2):554–557.
11. Andries K, Villellas C, Coeck N, et al. Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline. Plos ONE. 2014;9:e102135.
12. Santana M, Ionescu MS, Vertes A, et al. Bacillus subtilis F0F1 ATPase:DNA sequence of the atp operon and characterization of atp mutants. J Bacteriol. 1994;176:6802–6811.
13. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307:223–227.
14. Koul A, Vranckx L, Dendouga N, et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J Biol Chem. 2008;283:25273–25280.
15. Cook GM, Hards K, Vilchèze C, et al. Energetics of respiration and oxidative phosphorylation in mycobacteria. Microbiol Spectr. 2014;2(3). DOI:10.1128/microbiolspec.MGM2-0015-2013
16. Cox RA, Cook GM. Growth regulation in the mycobacterial cell. Curr Mol Med. 2007;7:231–245.
17. 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. 2008;105:11945–11950.
18. Fang J, Beattie DS. Novel FMN-containing rotenone-insensitive NADH dehydrogenase from Trypanosoma brucei mitochondria:isolation and characterization. Biochemistry. 2002;41:3065–3072.
19. Fisher N, Bray PG, Ward SA, et al. The malaria parasite type II NADH:quinone oxidoreductase:an alternative enzyme for an alternative lifestyle. Trends Parasitol. 2007;23:305–310.
20. Teh JS, Yano T, Rubin H. Type II NADH:menaquinone oxidoreductase of Mycobacterium tuberculosis. Infect Disord Drug Targets. 2007;7:169–181.
21. Cosma CL, Sherman DR, Ramakrishnan L. The secret lives of the pathogenic mycobacteria. Annu Rev Microbiol. 2003;57:641–676.
22. Koul A, Arnoult E, Lounis N, et al. The challenge of new drug discovery for tuberculosis. Nature. 2011;469:483–490.
23. Wayne LG, Sohaskey CD. Nonreplicating persistence of Mycobacterium tuberculosis. Annu Rev Microbiol. 2001;55:139–163.
24. Timm J, Post FA, Bekker L-G, et al. Differential expression of iron-, carbon-, and oxygen-responsive mycobacterial genes in the lungs of chronically infected mice and tuberculosis patients. Proc Natl Acad Sci. 2003;100:14321–14326.
25. Bald D, Koul A. Respiratory ATP synthesis:the new generation of mycobacterial drug targets? FEMS Microbiol Lett. 2010;308:1–7.
26. Berney M, Cook GM. Unique flexibility in energy metabolism allows mycobacteria to combat starvation and hypoxia. PLoS One. 2010;5:e8614.● This study has proved that mycobacteria can adapt to slow growth rate and hypoxia (i.e. dormancy) by using NADH dehydrogenase (NDH-2).
27. Gomez JE, McKinney JD. M. tuberculosis persistence, latency, and drug tolerance. Tuberculosis. 2004;84:29–44.
28. Bald D, Koul A. Advances and strategies in discovery of new antibacterials for combating metabolically resting bacteria. Drug Discovery Today. 2013;18:250–255.
29. Kerscher S, Dröse S, Zickermann V, et al. The three families of respiratory NADH dehydrogenases. Results Probl Cell Differ. 2008;45:185–222.
30. Heikal A, Nakatani Y, Dunn E, et al. Structure of the bacterial type II NADH dehydrogenase:a monotopic membrane protein with an essential role in energy generation. Mol Microbiol. 2014;91:950–964.
31. Neehaul Y, Juárez O, Barquera B, et al. Infrared spectroscopic evidence of a redox-dependent conformational change involving ion binding residue NqrB-D397 in the Na+-pumping NADH:quinone oxidoreductase from Vibrio cholerae. Biochemistry. 2013;52:3085–3093.
32. Novakovsky GE, Dibrova DV, Mulkidjanian AY. Phylogenomic analysis of type 1 NADH:quinone oxidoreductase. Biochemistry (Moscow). 2016;81:770–784.
33. Heikal A, Hards K, Cheung C-Y, et al. Activation of type II NADH dehydrogenase by quinolinequinones mediates antitubercular cell death. J Antimicrob Chemother. 2016;71(10):2840–2847.● This study has revealed quinolinequinones as potent inhibitors of NDH-2 in mycobacterial respiratory chain. They were also able to produce bactericidal effect against M. tuberculosis and M. bovis.
34. Young IG, Rogers BL, Campbell HD, et al. Nucleotide sequence coding for the respiratory NADH dehydrogenase of Escherichia coli. UUG Initiation Codon. Eur J Biochem. 1981;116:165–170.
35. Jaworowski A, Mayo G, Shaw DC, et al. Characterization of the respiratory NADH dehydrogenase of Escherichia coli and reconstitution of NADH oxidase in ndh mutant membrane vesicles. Biochemistry. 1981;20:3621–3628.
36. Sena FV, Batista AP, Catarino T, et al. Type‐II NADH:quinone oxidoreductase from Staphylococcus aureus has two distinct binding sites and is rate limited by quinone reduction. Mol Microbiol. 2015;98:272–288.
37. Yano T, Rahimian M, Aneja KK, et al. Mycobacterium tuberculosis type II NADH-menaquinone oxidoreductase catalyzes electron transfer through a two-site ping-pong mechanism and has two quinone-binding sites. Biochemistry. 2014;53:1179–1190.
38. Yang Y, Yamashita T, Nakamaru-Ogiso E, et al. Reaction mechanism of single subunit NADH-Ubiquinone Oxidoreductase (Ndi1) from Saccharomyces cerevisiae evidence for a ternary complex mechanism. J Biol Chem. 2011;286:9287–9297.
39. Weinstein EA, Yano T, Li L-S, et al. Inhibitors of type II NADH:menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci USA. 2005;102:4548–4553.● This paper has presented a detailed biochemical characterization of the aerobic respiratory chains from Mtb and show that phenothiazine analogs specifically inhibit NADH dehydrogenase activity.
40. Mogi T, Matsushita K, Murase Y, et al. Identification of new inhibitors for alternative NADH dehydrogenase (NDH-II). FEMS Microbiol Lett. 2009;291:157–161.
41. Kerscher SJ, Okun JG, Brandt U. A single external enzyme confers alternative NADH:ubiquinone oxidoreductase activity in Yarrowia lipolytica. ‎J Cell Sci. 1999;112:2347–2354.
42. Vries S, Grivell LA. Purification and characterization of a rotenone insensitive NADH:Q6 oxidoreductase from mitochondria of Saccharomyces cerevisiae. Eur J Biochem. 1988;176:377–384.
43. Biagini GA, Viriyavejakul P, O’neill PM, et al. Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria. Antimicrob Agents Chemother. 2006;50:1841–1851.
44. Björklöf K, Zickermann V, Finel M. Purification of the 45 kDa, membrane bound NADH dehydrogenase of Escherichia coli (NDH-2) and analysis of its interaction with ubiquinone analogues. FEBS Letters. 2000;467:105–110.
45. Salewski J, Batista AP, Sena FV, et al. Substrate-Protein Interactions of Type II NADH:quinone Oxidoreductase from Escherichia coli. Biochemistry. 2016;55:2722–2734.
46. Payne DJ, Gwynn MN, Holmes DJ, et al. Drugs for bad bugs:confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007;6:29–40.
47. Sharma U. Current possibilities and unresolved issues of drug target validation in Mycobacterium tuberculosis. Expert Opin Drug Discov. 2011;6:1171–1186.
48. Duncan K. Identification and validation of novel drug targets in tuberculosis. Curr Pharm Des. 2004;10:3185–3194.
49. Koul A, Dendouga N, Vergauwen K, et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat Chem Biol. 2007;3:323–324.
50. De Jonge MR, Koymans LH, Guillemont JE, et al. A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910. Proteins. 2007;67:971–980.
51. Vilcheze C, Weisbrod TR, Chen B, et al. Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria. Antimicrob Agents Chemother. 2005;49:708–720.
52. Barry CE, Boshoff HI, Dartois V, et al. The spectrum of latent tuberculosis:rethinking the biology and intervention strategies. Nature Rev Microbiol. 2009;7:845–855.
53. Schurig-Briccio LA, Yano T, Rubin H, et al. Characterization of the type 2 NADH:menaquinone oxidoreductases from Staphylococcus aureus and the bactericidal action of phenothiazines. Biochimica Et Biophysica Acta (Bba)-Bioenergetics. 2014;1837:954–963.
54. Young I, Jaworowski A, Poulis M. Amplification of the respiratory NADH dehydrogenase of Escherichia coli by gene cloning. Gene. 1978;4:25–36.
55. Miesel L, Weisbrod TR, Marcinkeviciene JA, et al. NADH dehydrogenase defects confer isoniazid resistance and conditional lethality in Mycobacterium smegmatis. ‎J Bacteriol. 1998;180:2459–2467.
56. Awasthy D, Ambady A, Narayana A, et al. Roles of the two type II NADH dehydrogenases in the survival of Mycobacterium tuberculosis in vitro. Gene. 2014;550:110–116.●● This is the very first description about the two genes ndh and ndhA for NDH-2 in Mtbgenome that eventually codes for two isozymes (Ndh and NdhA) of NDH-2. Where, Ndh is essential in ATP synthesis but NdhA is non-essential.
57. Shirude PS, Paul B, Roy Choudhury N, et al. Quinolinyl pyrimidines:potent inhibitors of NDH-2 as a novel class of anti-TB agents. ACS Med Chem Lett. 2012;3:736–740.● By this work, quinolinyl pyrimidines were identified as promising class of NDH-2inhibitors. Moreover, structure-activity relationship was established for further refinement of the lead molecules.
58. Fisher N, Warman AJ, Ward SA, et al. Type II NADH:quinone oxidoreductases of plasmodium falciparum and mycobacterium tuberculosis:kinetic and high-throughput assays. Methods Enzymol. 2009;456:303–320.
59. He C-X, Meng H, Zhang X, et al. Synthesis and bio-evaluation of phenothiazine derivatives as new anti-tuberculosis agents. Chin Chem Lett. 2015;26:951–954.
60. Bourdon J. Contribution to the study of the antibiotic properties of chlorpromazine or 4560 RP. Ann Inst Pasteur (Paris). 1961;101:876–886.
61. Kamińska M. Role of chlorpromazine in the treatment of pulmonary tuberculosis in psychiatric patients. Folia Medica Cracoviensia. 1966;9:115–143.
62. Amaral L, Martins A, Molnar J, et al. Phenothiazines, bacterial efflux pumps and targeting the macrophage for enhanced killing of intracellular XDRTB. In Vivo. 2010;24:409–424.
63. Amaral L, Molnar J. Potential therapy of multidrug-resistant and extremely drug-resistant tuberculosis with thioridazine. In Vivo. 2012;26:231–236.
64. Amaral L, Kristiansen JE, Viveiros M, et al. Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis:a review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy. J Antimicrob Chemother. 2001;47:505–511.
65. Gadre D, Talwar V, Gupta H, et al. Effect of trifluoperazine, a potential drug for tuberculosis with psychotic disorders, on the growth of clinical isolates of drug resistant Mycobactehum tuberculosis. Int Clin Psychopharmacol. 1998;13:129–132.
66. Crowle A, Douvas G, May M. Chlorpromazine:a drug potentially useful for treating mycobacterial infections. Chemotherapy. 1992;38:410–419.
67. Reddy MV, Nadadhur G, Gangadharam PRJ. In-vitro and intracellular antimycobacterial activity of trifluoperazine. J Antimicrob Chemother. 1996;37:196–197.
68. Van Soolingen D, Hernandez-Pando R, Orozco H, et al. The antipsychotic thioridazine shows promising therapeutic activity in a mouse model of multidrug-resistant tuberculosis. PLoS One. 2010;5:e12640.
69. Katoch VM, Saxena N, Shivannavar CT, et al. Effect of trifluoperazine on in vitro ATP synthesis by Mycobacterium leprae. FEMS Immunol Med Microbiol. 1998;20:99–102.
70. Amaral L, Viveiros M. Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections. Int J Antimicrob Agents. 2012;39:376–380.
71. Amaral L, Martins M, Viveiros M, et al. Promising therapy of XDR-TB/MDR-TB with thioridazine an inhibitor of bacterial efflux pumps. Curr Drug Targets. 2008;9:816–819.
72. Bate AB, Kalin JH, Fooksman EM, et al. Synthesis and antitubercular activity of quaternized promazine and promethazine derivatives. Bioorg Med Chem Lett. 2007;17:1346–1348.
73. Dunn EA, Roxburgh M, Larsen L, et al. Incorporation of triphenylphosphonium functionality improves the inhibitory properties of phenothiazine derivatives in Mycobacterium tuberculosis. Bioorg Med Chem. 2014;22:5320–5328.● This study has evaluated the potency of a series of phenothiazine derivatives against NDH-2 present in the mycobacterial membrane. It was found that the incorporation of triphenylphosphonium functionality has improved the inhibitory properties of phenothiazine derivatives.
74. Warman AJ, Rito T, Fisher N, et al. The type II NADH:quinone oxidoreductase of Mycobacterium tuberculosis:a novel drug target for an age-old problem. Biochimica Et Biophysica Acta (Bba)-Bioenergetics. 2010;1797(Supplement):117–118.
75. Mulchin BJ, Newton CG, Baty JW, et al. The anti-cancer, anti-inflammatory and tuberculostatic activities of a series of 6, 7-substituted-5, 8-quinolinequinones. Bioorg Med Chem. 2010;18:3238–3251.
76. 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. 2012;64:4–17.
77. Dunn EA, Cook GM, Heikal A. Comparison of lipid and detergent enzyme environments for identifying inhibitors of membrane-bound energy-transducing proteins. J Microbiol Methods. 2016;120:41–43.
78. Dunn EA, Cook GM, Heikal A. Annotated compound data for modulators of detergent-solubilised or lipid-reconstituted respiratory type II NADH dehydrogenase activity obtained by compound library screening. Data in Brief. 2016;6:275–278.
79. Jünemann S. Cytochrome bd terminal oxidase. Biochimica Et Biophysica Acta (Bba)-Bioenergetics. 1997;1321:107–127.
80. Mogi T. Two terminal quinol oxidase families in Escherichia coli:variations on molecular machinery for dioxygen reduction. J Biochem Mol Biol Biophys. 1998;2:79–110.
81. Ui H, Ishiyama A, Sekiguchi H, et al. Selective and potent in vitro antimalarial activities found in four microbial metabolites. J Antibiot. 2007;60:220.
82. Mogi T, Ui H, Shiomi K, et al. Gramicidin S identified as a potent inhibitor for cytochrome bd-type quinol oxidase. FEBS Letters. 2008;582:2299–2302.
83. Yano T, Li L-S, Weinstein E, et al. Steady-state kinetics and inhibitory action of antitubercular phenothiazines on Mycobacterium tuberculosis type-II NADH-menaquinone oxidoreductase (NDH-2). J Biol Chem. 2006;281:11456–11463.●● An excellent work that explains the ping-pong mechanism of NDH-2. The inhibition of NDH-2 by trifluoperazine was found noncompetitive to NADH but was uncompetitive to quinone.
84. Yano T, Kassovska-Bratinova S, Teh JS, et al. Reduction of clofazimine by mycobacterial type 2 NADH:quinone oxidoreductase:a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem. 2011;286:10276–10287.
85. Zumla AI, Gillespie SH, Hoelscher M, et al. New antituberculosis drugs, regimens, and adjunct therapies:needs, advances, and future prospects. Lancet Infect Dis. 2014;14:327–340.
86. Melo AMP, Bandeiras TM, Teixeira M. New insights into type II NAD(P)H:quinone oxidoreductases. Microbiol Mol Biol Rev. 2004;68:603–616.
87. Vesenbeckh S, Krieger D, Bettermann G, et al. Neuroleptic drugs in the treatment of tuberculosis:minimal inhibitory concentrations of different phenothiazines against Mycobacterium tuberculosis. Tuberculosis. 2016;98:27–29.