Towards a New Tuberculosis Drug: Pyridomycin - Nature's Isoniazid

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2012 Sep 19

PMID 22987724

Citations 77

Authors

Ruben C Hartkoorn

Claudia Sala

Joao Neres

Florence Pojer

Sophie Magnet

Raju Mukherjee

Swapna Uplekar

Stefanie Boy-Rottger

Karl-Heinz Altmann

Stewart T Cole

Affiliations

Soon will be listed here.

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

Palomino J, 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(8):2720-2. PMC: 127336. DOI: 10.1128/AAC.46.8.2720-2722.2002. View

Lamichhane G . Novel targets in M. tuberculosis: search for new drugs. Trends Mol Med. 2010; 17(1):25-33. DOI: 10.1016/j.molmed.2010.10.004. View

YAGISHITA K . Studies on the pyridomycin production. IV. Metabolic studies on Streptomyces pyridomyceticus. J Antibiot (Tokyo). 1957; 10(1):15-20. View

Quemard A, Sacchettini J, Dessen A, Vilcheze C, Bittman R, Jacobs Jr W . Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry. 1995; 34(26):8235-41. DOI: 10.1021/bi00026a004. View

Baldock C, Rafferty J, Sedelnikova S, Baker P, Stuitje A, Slabas A . A mechanism of drug action revealed by structural studies of enoyl reductase. Science. 1996; 274(5295):2107-10. DOI: 10.1126/science.274.5295.2107. View

Larsen M, Vilcheze C, Kremer L, Besra G, Parsons L, Salfinger M . Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Mol Microbiol. 2002; 46(2):453-66. DOI: 10.1046/j.1365-2958.2002.03162.x. View

Molle V, Gulten G, Vilcheze C, Veyron-Churlet R, Zanella-Cleon I, Sacchettini J . Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis. Mol Microbiol. 2010; 78(6):1591-605. DOI: 10.1111/j.1365-2958.2010.07446.x. View

Freundlich J, Wang F, Vilcheze C, Gulten G, Langley R, Schiehser G . Triclosan derivatives: towards potent inhibitors of drug-sensitive and drug-resistant Mycobacterium tuberculosis. ChemMedChem. 2009; 4(2):241-8. PMC: 3541007. DOI: 10.1002/cmdc.200800261. View

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

10.

Harrington M . From HIV to tuberculosis and back again: a tale of activism in 2 pandemics. Clin Infect Dis. 2010; 50 Suppl 3:S260-6. DOI: 10.1086/651500. View

11.

Vilcheze C, Baughn A, Tufariello J, Leung L, Kuo M, Basler C . Novel inhibitors of InhA efficiently kill Mycobacterium tuberculosis under aerobic and anaerobic conditions. Antimicrob Agents Chemother. 2011; 55(8):3889-98. PMC: 3147652. DOI: 10.1128/AAC.00266-11. View

12.

Winn M, Ballard C, Cowtan K, Dodson E, Emsley P, Evans P . Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 4):235-42. PMC: 3069738. DOI: 10.1107/S0907444910045749. View

13.

Cole S, Riccardi G . New tuberculosis drugs on the horizon. Curr Opin Microbiol. 2011; 14(5):570-6. DOI: 10.1016/j.mib.2011.07.022. View

14.

Zhang Y, Rock C . Membrane lipid homeostasis in bacteria. Nat Rev Microbiol. 2008; 6(3):222-33. DOI: 10.1038/nrmicro1839. View

15.

Ogawara H, Maeda K, Umezawa H . The biosynthesis of pyridomycin. I. Biochemistry. 1968; 7(9):3296-302. DOI: 10.1021/bi00849a037. View

16.

YAGISHITA K . Studies on the pyridomycin production. III. Medium selection and a device of a method of detecting the precursor. J Antibiot (Tokyo). 1957; 10(1):5-14. View

17.

Payne D, Gwynn M, Holmes D, Pompliano D . Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2006; 6(1):29-40. DOI: 10.1038/nrd2201. View

18.

Morlock G, Metchock B, Sikes D, Crawford J, Cooksey R . ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother. 2003; 47(12):3799-805. PMC: 296216. DOI: 10.1128/AAC.47.12.3799-3805.2003. View

19.

Parikh S, Xiao G, Tonge P . Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid. Biochemistry. 2000; 39(26):7645-50. DOI: 10.1021/bi0008940. View

20.

Heath R, White S, Rock C . Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl Microbiol Biotechnol. 2002; 58(6):695-703. DOI: 10.1007/s00253-001-0918-z. View