Towards a new tuberculosis drug: pyridomycin – nature's isoniazid

Abstract

Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. →See accompanying article http://dx.doi.org/10.1002/emmm.201201811.

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References 48

1. 1.

   Baldock C, Rafferty JB, Sedelnikova SE, Baker PJ, Stuitje AR, Slabas AR, Hawkes TR, Rice DW. A mechanism of drug action revealed by structural studies of enoyl reductase. Science. 1996;274:2107-2110.

   Not in our library10.1126/science.274.5295.2107

2. 2.

   Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, Collins D, de Lisle G, Jacobs WR. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994;263:227-230.

   Not in our library10.1126/science.8284673

3. 3.

   Cegielski JP. Extensively drug-resistant tuberculosis: “There must be some kind of way out of here”. Clin Infect Dis. 2010;50:S195-S200.

   Not in our library10.1086/651491

4. 4.

   Cole ST, Brosch R, Parkhill J, Garnier T, Churcher C, Harris D, Gordon SV, Eiglmeier K, Gas S, Barry CE, et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature. 1998;393:537-544.

   Not in our library10.1038/31159

5. 5.

   Cole ST, Riccardi G. New tuberculosis drugs on the horizon. Curr Opin Microbiol. 2011;14:570-576.

   Not in our library10.1016/j.mib.2011.07.022

6. 6.

   Dessen A, Quemard A, Blanchard JS, Jacobs WR, Sacchettini JC. Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Science. 1995;267:1638-1641.

   Not in our library10.1126/science.7886450

7. 7.

   Dias MV, Vasconcelos IB, Prado AM, Fadel V, Basso LA, de Azevedo WF, Santos DS. Crystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis. J Struct Biol. 2007;159:369-380.

   Not in our library10.1016/j.jsb.2007.04.009

8. 8.

   Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009;325:1089-1093.

   Not in our library10.1126/science.1176667

9. 9.

   Freundlich JS, Wang F, Vilcheze C, Gulten G, Langley R, Schiehser GA, Jacobus DP, Jacobs WR, Sacchettini JC. Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis. ChemMedChem. 2009;4:241-248.

   Not in our library10.1002/cmdc.200800261

10. 10.

    Glaziou P, Floyd K, Raviglione M. Global burden and epidemiology of tuberculosis. Clin Chest Med. 2009;30:621-636.

    Not in our library10.1016/j.ccm.2009.08.017

11. 11.

    Harrington M. From HIV to tuberculosis and back again: a tale of activism in 2 pandemics. Clin Infect Dis. 2010;50:S260-S266.

    Not in our library10.1086/651500

12. 12.

    Heath RJ, White SW, Rock CO. Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl Microbiol Biotechnol. 2002;58:695-703.

    Not in our library10.1007/s00253-001-0918-z

13. 13.

    Huang TT, Wang YM, Yin J, Du YH, Tao MF, Xu J, Chen WQ, Lin SJ, Deng ZX. Identification and characterization of the pyridomycin biosynthetic gene cluster of Streptomyces pyridomyceticus NRRL B-2517. J Biol Chem. 2011;286:20648-20657.

    Not in our library10.1074/jbc.m110.180000

14. 14.
    XDS · 2010

    No notice
15. 15.

    Kinoshita M, Nakata M, Takarada K, Tatsuta K. Synthetic studies of pyridomycin 5. Total synthesis of pyridomycin. Tetrahedron Lett. 1989;30:7419-7422.

    Not in our library

16. 16.

    Lamichhane G. Novel targets in M. tuberculosis: search for new drugs. Trends Mol Med. 2011;17:25-33.

    Not in our library10.1016/j.molmed.2010.10.004

17. 17.

    Larsen MH, Vilcheze C, Kremer L, Besra GS, Parsons L, Salfinger M, Heifets L, Hazbon MH, Alland D, Sacchettini JC, et al. Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatisM. bovis BCG and M. tuberculosis. Mol Microbiol. 2002;46:453-466.

    Not in our library10.1046/j.1365-2958.2002.03162.x

18. 18.

    Laskowski RA, Rullmannn JA, MacArthur MW, Kaptein R, Thornton JM. AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR. 1996;8:477-486.

    Not in our library10.1007/bf00228148

19. 19.

    Lu H, Tonge PJ. Inhibitors of FabI, an enzyme drug target in the bacterial fatty acid biosynthesis pathway. Acc Chem Res. 2008;41:11-20.

    Not in our library10.1021/ar700156e

20. 20.

    Maeda K. Degradation studies on pyridomycin; chemical studies on antibiotics of Streptomyces. V. J Antibiot (Tokyo). 1957;10:94-106.

    Not in our library

21. 21.

    Maeda K, Kosaka H, Okami Y, Umezawa H. A new antibiotic, pyridomycin. J Antibiot (Tokyo). 1953;6:140.

    Not in our library

22. 22.
    Phaser crystallographic software · 2007

    No notice
23. 23.

    McMurry LM, Oethinger M, Levy SB. Triclosan targets lipid synthesis. Nature. 1998;394:531-532.

    Not in our library10.1038/28970

24. 24.

    Molle V, Gulten G, Vilcheze C, Veyron-Churlet R, Zanella-Cleon I, Sacchettini JC, Jacobs WR, Kremer L. Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis. Mol Microbiol. 2010;78:1591-1605.

    Not in our library10.1111/j.1365-2958.2010.07446.x

25. 25.

    Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC. ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother. 2003;47:3799-3805.

    Not in our library10.1128/aac.47.12.3799-3805.2003

26. 26.

    Murshudov GN, Vagin AA, Dodson EJ. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr. 1997;53:240-255.

    Not in our library10.1107/s0907444996012255

27. 27.

    Ogawara H, Maeda K, Umezawa H. The biosynthesis of pyridomycin. I. Biochemistry. 1968;7:3296-3302.

    Not in our library10.1021/bi00849a037

28. 28.

    Oliveira JS, Pereira JH, Canduri F, Rodrigues NC, de Souza ON, de Azevedo WF, Basso LA, Santos DS. Crystallographic and pre-steady-state kinetics studies on binding of NADH to wild-type and isoniazid-resistant enoyl-ACP (CoA) reductase enzymes from Mycobacterium tuberculosis. J Mol Biol. 2006;359:646-666.

    Not in our library10.1016/j.jmb.2006.03.055

29. 29.

    Palomino JC, Martin A, Camacho M, Guerra H, Swings J, Portaels F. Resazurin microtiter assay plate: simple and inexpensive method for detection of drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2002;46:2720-2722.

    Not in our library10.1128/aac.46.8.2720-2722.2002

30. 30.

    Parikh SL, Xiao G, Tonge PJ. Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid. Biochemistry. 2000;39:7645-7650.

    Not in our library10.1021/bi0008940

31. 31.

    Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007;6:29-40.

    Not in our library10.1038/nrd2201

32. 32.

    Payne DJ, Miller WH, Berry V, Brosky J, Burgess WJ, Chen E, DeWolf WE, Fosberry AP, Greenwood R, Head MS, et al. Discovery of a novel and potent class of FabI-directed antibacterial agents. Antimicrob Agents Chemother. 2002;46:3118-3124.

    Not in our library10.1128/aac.46.10.3118-3124.2002

33. 33.

    Quemard A, Sacchettini JC, Dessen A, Vilcheze C, Bittman R, Jacobs WR, Blanchard JS. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry. 1995;34:8235-8241.

    Not in our library10.1021/bi00026a004

34. 34.

    Rawat R, Whitty A, Tonge PJ. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc Natl Acad Sci USA. 2003;100:13881-13886.

    Not in our library10.1073/pnas.2235848100

35. 35.

    Rozwarski DA, Vilcheze C, Sugantino M, Bittman R, Sacchettini JC. Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. J Biol Chem. 1999;274:15582-15589.

    Not in our library10.1074/jbc.274.22.15582

36. 36.

    Sala C, Dhar N, Hartkoorn RC, Zhang M, Ha YH, Schneider P, Cole ST. Simple model for testing drugs against nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2010;54:4150-4158.

    Not in our library10.1128/aac.00821-10

37. 37.

    Shomura T, Amano S, Yoshida J, Kojima M. Dactylosporangium-fulvum Sp-Nov. Int J Syst Bacteriol. 1986;36:166-169.

    Not in our library

38. 38.

    Smith PA, Roberts TC, Romesberg FE. Broad-spectrum antibiotic activity of the arylomycin natural products is masked by natural target mutations. Chem Biol. 2010;17:1223-1231.

    Not in our library10.1016/j.chembiol.2010.09.009

39. 39.

    Sullivan TJ, Truglio JJ, Boyne ME, Novichenok P, Zhang X, Stratton CF, Li HJ, Kaur T, Amin A, Johnson F, et al. High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis. ACS Chem Biol. 2006;1:43-53.

    Not in our library10.1021/cb0500042

40. 40.

    Vilcheze C, Baughn AD, Tufariello J, Leung LW, Kuo M, Basler CF, Alland D, Sacchettini JC, Freundlich JS, Jacobs WR. Novel inhibitors of InhA efficiently kill Mycobacterium tuberculosis under aerobic and anaerobic conditions. Antimicrob Agents Chemother. 2011;55:3889-3898.

    Not in our library10.1128/aac.00266-11

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