A novel small-molecule inhibitor of the mycobacterium tuberculosis demethylmenaquinone methyltransferase meng is bactericidal to both growing and nutritionally deprived persister cells

mBio

Volumn 8, Issue 1, 2017, Pages

  Sukheja, Paridhi ^a   Kumar, Pradeep ^a   Mittal, Nisha ^b   Li, Shao Gang ^b   Singleton, Eric ^a   Russo, Riccardo ^a   Perryman, Alexander L ^b   Shrestha, Riju ^a   Awasthi, Divya ^b   Husain, Seema ^a   Soteropoulos, Patricia ^a   Brukh, Roman ^c   Connell, Nancy ^a   Freundlich, Joel S ^a,b   Alland, David ^a  

^a RUTGERS NEW JERSEY MEDICAL SCHOOL   (United States)

^b RUTGERS UNIVERSITY   (United States)

^c Rutgers The State University of New Jersey   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; BACTERIAL PROTEIN; BEDAQUILINE; DG 70; ISONIAZID; MENAQUINONE; MENG PROTEIN; METHYLTRANSFERASE; RIFAMPICIN; TUBERCULOSTATIC AGENT; UNCLASSIFIED DRUG; BIPHENYL DERIVATIVE; DEMETHYLMENAQUINONE; FARNOQUINONE; MOLECULAR LIBRARY;

ANTIBIOTIC RESISTANCE; ARTICLE; BACTERIAL GENE; BACTERIAL GENOME; BACTERIAL STRAIN; BACTERICIDAL ACTIVITY; BACTERIUM COLONY; BACTERIUM CULTURE; BIOSYNTHESIS; DRUG POTENTIATION; DRUG RESISTANT TUBERCULOSIS; DRUG SCREENING; GENE MUTATION; GENE OVEREXPRESSION; ISOTOPE LABELING; MASS SPECTROMETRY; MENG GENE; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; OXYGEN CONSUMPTION; WHOLE GENOME SEQUENCING; WILD TYPE; ANALOGS AND DERIVATIVES; ANALYSIS; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; ENZYMOLOGY; GROWTH, DEVELOPMENT AND AGING; HUMAN; ISOLATION AND PURIFICATION; METABOLISM; MICROBIAL SENSITIVITY TEST; MOLECULAR LIBRARY;

ADENOSINE TRIPHOSPHATE; ANTITUBERCULAR AGENTS; BIPHENYL COMPOUNDS; DRUG DISCOVERY; DRUG RESISTANCE, BACTERIAL; HUMANS; METHYLTRANSFERASES; MICROBIAL SENSITIVITY TESTS; MYCOBACTERIUM TUBERCULOSIS; SMALL MOLECULE LIBRARIES; VITAMIN K 2;

EID: 85014816484     PISSN: 21612129     EISSN: 21507511     Source Type: Journal    
DOI: 10.1128/mBio.02022-16     Document Type: Article

References (37)

1. World Health Organization. 2014. Global tuberculosis report 2014. World Health Organization, Geneva, Switzerland.
2. Riccardi G, Pasca MR. 2014. Trends in discovery of new drugs for tuberculosis therapy. J Antibiot (Tokyo) 67:655–659. https://doi.org/10.1038/ja.2014.109.
3. Walter ND, Dolganov GM, Garcia BJ, Worodria W, Andama A, Musisi E, Ayakaka I, Van TT, Voskuil MI, de Jong BC, Davidson RM, Fingerlin TE, Kechris K, Palmer C, Nahid P, Daley CL, Geraci M, Huang L, Cattamanchi A, Strong M, Schoolnik GK, Davis JL. 2015. Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis. J Infect Dis 212:990–998. https://doi.org/10.1093/infdis/jiv149.
4. Rao SPS, Alonso S, Rand L, Dick T, Pethe K. 2008. The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 105:11945–11950. https://doi.org/10.1073/pnas.0711697105.
5. Fattorini L, Piccaro G, Mustazzolu A, Giannoni F. 2013. Targeting dormant bacilli to fight tuberculosis. Mediterr J Hematol Infect Dis 5:e2013072. https://doi.org/10.4084/MJHID.2013.072.
6. Sacchettini JC, Rubin EJ, Freundlich JS. 2008. Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. Nat Rev Microbiol 6:41–52. https://doi.org/10.1038/nrmicro1816.
7. Haagsma AC, Driessen NN, Hahn MM, Lill H, Bald D. 2010. ATP synthase in slow- and fast-growing mycobacteria is active in ATP synthesis and blocked in ATP hydrolysis direction. FEMS Microbiol Lett 313:68–74. https://doi.org/10.1111/j.1574-6968.2010.02123.x.
8. Bald D, Koul A. 2010. Respiratory ATP synthesis: the new generation of mycobacterial drug targets? FEMS Microbiol Lett 308:1–7. https://doi.org/10.1111/j.1574-6968.2010.01959.x.
9. Cook GM, Hards K, Vilchèze C, Hartman T, Berney M. 2014. Energetics of respiration and oxidative phosphorylation in mycobacteria. Microbiol Spectr 2(3). https://doi.org/10.1128/microbiolspec.MGM2-0015-2013.
10. Kint CI, Verstraeten N, Fauvart M, Michiels J. 2012. New-found fundamentals of bacterial persistence. Trends Microbiol 20:577–585. https://doi.org/10.1016/j.tim.2012.08.009.
11. Drusano GL, Neely M, Van Guilder M, Schumitzky A, Brown D, Fikes S, Peloquin C, Louie A. 2014. Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis. PLoS One 9:e101311. https://doi.org/10.1371/journal.pone.0101311.
12. Berney M, Berney-Meyer L, Wong KW, Chen B, Chen M, Kim J, Wang J, Harris D, Parkhill J, Chan J, Wang F, Jacobs WR, Jr. 2015. Essential roles of methionine and S-adenosylmethionine in the autarkic lifestyle of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 112:10008–10013. https://doi.org/10.1073/pnas.1513033112.
13. Cook GM, Greening C, Hards K, Berney M. 2014. Energetics of pathogenic bacteria and opportunities for drug development. Adv Microb Physiol 65:1–62. https://doi.org/10.1016/bs.ampbs.2014.08.001.
14. Jirgis EN, Bashiri G, Bulloch EM, Johnston JM, Baker EN. 2016. Structural views along the Mycobacterium tuberculosis MenD reaction pathway illuminate key aspects of thiamin diphosphate-dependent enzyme mechanisms. Structure 24:1167–1177. https://doi.org/10.1016/j.str.2016.04.018.
15. Upadhyay A, Fontes FL, Gonzalez-Juarrero M, McNeil MR, Crans DC, Jackson M, Crick DC. 2015. Partial saturation of menaquinone in Mycobacterium tuberculosis: function and essentiality of a novel reductase, MenJ. ACS Cent Sci 1:292–302. https://doi.org/10.1021/acscentsci.5b00212.
16. Dhiman RK, Mahapatra S, Slayden RA, Boyne ME, Lenaerts A, Hinshaw JC, Angala SK, Chatterjee D, Biswas K, Narayanasamy P, Kurosu M, Crick DC. 2009. Menaquinone synthesis is critical for maintaining mycobacterial viability during exponential growth and recovery from non-replicating persistence. Mol Microbiol 72:85–97. https://doi.org/10.1111/j.1365 -2958.2009.06625.x.
17. Ballell L, Bates RH, Young RJ, Alvarez-Gomez D, Alvarez-Ruiz E, Barroso V, Blanco D, Crespo B, Escribano J, González R, Lozano S, Huss S, Santos-Villarejo A, Martín-Plaza JJ, Mendoza A, Rebollo-Lopez MJ, Remuiñan-Blanco M, Lavandera JL, Pérez-Herran E, Gamo-Benito FJ, García-Bustos JF, Barros D, Castro JP, Cammack N. 2013. Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis. ChemMed-Chem 8:313–321. https://doi.org/10.1002/cmdc.201200428.
18. Wilson R, Kumar P, Parashar V, Vilchèze C, Veyron-Churlet R, Freundlich JS, Barnes SW, Walker JR, Szymonifka MJ, Marchiano E, Shenai S, Colan-geli R, Jacobs WR, Jr., Neiditch MB, Kremer L, Alland D. 2013. Antituber-culosis thiophenes define a requirement for Pks13 in mycolic acid biosynthesis. Nat Chem Biol 9:499–506. https://doi.org/10.1038/nchembio.1277.
19. Boshoff HI, Myers TG, Copp BR, McNeil MR, Wilson MA, Barry CE, III. 2004. The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem 279:40174–40184. https://doi.org/10.1074/jbc.M406796200.
20. Kana BD, Weinstein EA, Avarbock D, Dawes SS, Rubin H, Mizrahi V. 2001. Characterization of the cydAB-encoded cytochrome bd oxidase from Mycobacterium smegmatis. J Bacteriol 183:7076–7086. https://doi.org/10.1128/JB.183.24.7076-7086.2001.
21. Weinstein EA, Yano T, Li LS, Avarbock D, Avarbock A, Helm D, McColm AA, Duncan K, Lonsdale JT, Rubin H. 2005. Inhibitors of type II NADH: menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci U S A 102:4548–4553. https://doi.org/10.1073/pnas.0500469102.
22. Manjunatha U, Boshoff HI, Barry CE. 2009. The mechanism of action of PA-824: novel insights from transcriptional profiling. Commun Integr Biol 2:215–218. https://doi.org/10.4161/cib.2.3.7926.
23. Koul A, Vranckx L, Dhar N, Göhlmann HW, Özdemir E, Neefs JM, Schulz M, Lu P, Mørtz E, McKinney JD, Andries K, Bald D. 2014. Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism. Nat Commun 5:3369. https://doi.org/10.1038/ncomms4369.
24. Schön T, Juréen P, Giske CG, Chryssanthou E, Sturegård E, Werngren J, Kahlmeter G, Hoffner SE, Angeby KA. 2009. Evaluation of wild-type MIC distributions as a tool for determination of clinical breakpoints for Mycobacterium tuberculosis. J Antimicrob Chemother 64:786–793. https://doi.org/10.1093/jac/dkp262.
25. Sassetti CM, Boyd DH, Rubin EJ. 2003. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol 48:77–84. https://doi.org/10.1046/j.1365-2958.2003.03425.x.
26. Kurosu M, Begari E. 2010. Vitamin K2 in electron transport system: are enzymes involved in vitamin K2 biosynthesis promising drug targets? Molecules 15:1531–1553. https://doi.org/10.3390/molecules15031531.
27. Gengenbacher M, Rao SP, Pethe K, Dick T. 2010. Nutrient-starved, non-replicating Mycobacterium tuberculosis requires respiration, ATP synthase and isocitrate lyase for maintenance of ATP homeostasis and viability. Microbiology 156:81–87. https://doi.org/10.1099/mic.0.033084-0.
28. Honaker RW, Dhiman RK, Narayanasamy P, Crick DC, Voskuil MI. 2010. DosS responds to a reduced electron transport system to induce the Mycobacterium tuberculosis DosR regulon. J Bacteriol 192:6447–6455. https://doi.org/10.1128/JB.00978-10.
29. Debnath J, Siricilla S, Wan B, Crick DC, Lenaerts AJ, Franzblau SG, Kurosu M. 2012. Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. J Med Chem 55:3739–3755. https://doi.org/10.1021/jm201608g.
30. Blomberg B, Spinaci S, Fourie B, Laing R. 2001. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ 79:61–68.
31. Hsieh MH, Yu CM, Yu VL, Chow JW. 1993. Synergy assessed by checkerboard. A critical analysis. Diagn Microbiol Infect Dis 16:343–349. https://doi.org/10.1016/0732-8893(93)90087-N.
32. Rastogi N, Goh KS, Horgen L, Barrow WW. 1998. Synergistic activities of antituberculous drugs with cerulenin and trans-cinnamic acid against Mycobacterium tuberculosis. FEMS Immunol Med Microbiol 21:149–157. https://doi.org/10.1111/j.1574-695X.1998.tb01161.x.
33. Matarlo JS, Evans CE, Sharma I, Lavaud LJ, Ngo SC, Shek R, Rajashankar KR, French JB, Tan DS, Tonge PJ. 2015. Mechanism of MenE inhibition by acyl-adenylate analogues and discovery of novel antibacterial agents. Biochemistry 54:6514–6524. https://doi.org/10.1021/acs.biochem.5b00966.
34. Honaker RW, Leistikow RL, Bartek IL, Voskuil MI. 2009. Unique roles of DosT and DosS in DosR regulon induction and Mycobacterium tuberculosis dormancy. Infect Immun 77:3258–3263. https://doi.org/10.1128/IAI.01449-08.
35. Lechartier B, Hartkoorn RC, Cole ST. 2012. In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. Antimicrob Agents Chemother 56:5790–5793. https://doi.org/10.1128/AAC.01476-12.
36. Hall MJ, Middleton RF, Westmacott D. 1983. The fractional inhibitory concentration (FIC) index as a measure of synergy. J Antimicrob Chemother 11:427–433. https://doi.org/10.1093/jac/11.5.427.
37. Betts JC, Lukey PT, Robb LC, McAdam RA, Duncan K. 2002. Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Mol Microbiol 43:717–731. https://doi.org/10.1046/j.1365-2958.2002.02779.x.