2ntj › Citations

Mechanism of thioamide drug action against tuberculosis and leprosy.

Figure 1.
Figure 2.
Figure 3.
Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WR, Sacchettini JC
OpenAccess logo J Exp Med 204 73-8 (2007)
Related entries: 2h9i, 2ntv

Cited: 112 times
EuropePMC logo PMID: 17227913

Abstract

Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target-drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.

Articles - 2ntj mentioned but not cited (1)

  1. An Effective Approach for Clustering InhA Molecular Dynamics Trajectory Using Substrate-Binding Cavity Features. De Paris R, Quevedo CV, Ruiz DD, Norberto de Souza O. PLoS One 10 e0133172 (2015)


Reviews citing this publication (39)

  1. Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs. Almeida Da Silva PE, Palomino JC. J Antimicrob Chemother 66 1417-1430 (2011)
  2. Drugs versus bugs: in pursuit of the persistent predator Mycobacterium tuberculosis. Sacchettini JC, Rubin EJ, Freundlich JS. Nat Rev Microbiol 6 41-52 (2008)
  3. The Concept of an Ideal Antibiotic: Implications for Drug Design. Gajdács M. Molecules 24 E892 (2019)
  4. Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis: Genes, Mutations, and Causalities. Vilchèze C, Jacobs WR. Microbiol Spectr 2 MGM2-0014-2013 (2014)
  5. Antibacterial targets in fatty acid biosynthesis. Wright HT, Reynolds KA. Curr Opin Microbiol 10 447-453 (2007)
  6. New approaches to target the mycolic acid biosynthesis pathway for the development of tuberculosis therapeutics. North EJ, Jackson M, Lee RE. Curr Pharm Des 20 4357-4378 (2014)
  7. Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis. Shastri MD, Shukla SD, Chong WC, Dua K, Peterson GM, Patel RP, Hansbro PM, Eri R, O'Toole RF. Oxid Med Cell Longev 2018 7695364 (2018)
  8. Tuberculosis: drug resistance, fitness, and strategies for global control. Böttger EC, Springer B. Eur J Pediatr 167 141-148 (2008)
  9. Clinical value of whole-genome sequencing of Mycobacterium tuberculosis. Takiff HE, Feo O. Lancet Infect Dis 15 1077-1090 (2015)
  10. Mycobacterium tuberculosis: drug resistance and future perspectives. Riccardi G, Pasca MR, Buroni S. Future Microbiol 4 597-614 (2009)
  11. Safety and tolerability profile of second-line anti-tuberculosis medications. Ramachandran G, Swaminathan S. Drug Saf 38 253-269 (2015)
  12. Clinical pharmacology and lesion penetrating properties of second- and third-line antituberculous agents used in the management of multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis. Dartois V, Barry CE. Curr Clin Pharmacol 5 96-114 (2010)
  13. Recent advances in inhibitors of bacterial fatty acid synthesis type II (FASII) system enzymes as potential antibacterial agents. Wang Y, Ma S. ChemMedChem 8 1589-1608 (2013)
  14. Anaerobic bacteria as producers of antibiotics. Behnken S, Hertweck C. Appl Microbiol Biotechnol 96 61-67 (2012)
  15. Targeting tuberculosis using structure-guided fragment-based drug design. Mendes V, Blundell TL. Drug Discov Today 22 546-554 (2017)
  16. New prodrugs against tuberculosis. Mori G, Chiarelli LR, Riccardi G, Pasca MR. Drug Discov Today 22 519-525 (2017)
  17. Strategies for potentiation of ethionamide and folate antagonists against Mycobacterium tuberculosis. Wolff KA, Nguyen L. Expert Rev Anti Infect Ther 10 971-981 (2012)
  18. Addressing the Challenges of Tuberculosis: A Brief Historical Account. Al-Humadi HW, Al-Saigh RJ, Al-Humadi AW. Front Pharmacol 8 689 (2017)
  19. Antibiotic resistance genes in the Actinobacteria phylum. Fatahi-Bafghi M. Eur J Clin Microbiol Infect Dis 38 1599-1624 (2019)
  20. Microbial transformation of azaarenes and potential uses in pharmaceutical synthesis. Parshikov IA, Netrusov AI, Sutherland JB. Appl Microbiol Biotechnol 95 871-889 (2012)
  21. Update of Antitubercular Prodrugs from a Molecular Perspective: Mechanisms of Action, Bioactivation Pathways, and Associated Resistance. Laborde J, Deraeve C, Bernardes-Génisson V. ChemMedChem 12 1657-1676 (2017)
  22. Synthetic biology in the analysis and engineering of signaling processes. Kämpf MM, Weber W. Integr Biol (Camb) 2 12-24 (2010)
  23. New drugs and vaccines for drug-resistant Mycobacterium tuberculosis infections. Dover LG, Bhatt A, Bhowruth V, Willcox BE, Besra GS. Expert Rev Vaccines 7 481-497 (2008)
  24. Recycling and refurbishing old antitubercular drugs: the encouraging case of inhibitors of mycolic acid biosynthesis. Belardinelli JM, Morbidoni HR. Expert Rev Anti Infect Ther 11 429-440 (2013)
  25. Strategies towards the synthesis of anti-tuberculosis drugs. Rode HB, Lade DM, Grée R, Mainkar PS, Chandrasekhar S. Org Biomol Chem 17 5428-5459 (2019)
  26. Nucleoside analogs and tuberculosis: new weapons against an old enemy. Ferrari V, Serpi M. Future Med Chem 7 291-314 (2015)
  27. Ethionamide. Tuberculosis (Edinb) 88 106-108 (2008)
  28. Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review. Timo GO, Reis RSSVD, Melo AF, Costa TVL, Magalhães PO, Homem-de-Mello M. Pharmaceuticals (Basel) 12 E135 (2019)
  29. Prothionamide. Tuberculosis (Edinb) 88 139-140 (2008)
  30. Treatment of tuberculosis in children. Cruz AT, Starke JR. Expert Rev Anti Infect Ther 6 939-957 (2008)
  31. Implications of Fragment-Based Drug Discovery in Tuberculosis and HIV. Mallakuntla MK, Togre NS, Santos DB, Tiwari S. Pharmaceuticals (Basel) 15 1415 (2022)
  32. The Prospective Synergy of Antitubercular Drugs With NAD Biosynthesis Inhibitors. Rohde KH, Sorci L. Front Microbiol 11 634640 (2020)
  33. Molecular Mechanisms of MmpL3 Function and Inhibition. Williams JT, Abramovitch RB. Microb Drug Resist 29 190-212 (2023)
  34. Structure-Guided Computational Approaches to Unravel Druggable Proteomic Landscape of Mycobacterium leprae. Vedithi SC, Malhotra S, Acebrón-García-de-Eulate M, Matusevicius M, Torres PHM, Blundell TL. Front Mol Biosci 8 663301 (2021)
  35. The pathogenic mechanism of Mycobacterium tuberculosis: implication for new drug development. Yan W, Zheng Y, Dou C, Zhang G, Arnaout T, Cheng W. Mol Biomed 3 48 (2022)
  36. Mycobacterium tuberculosis: Pathogenesis and therapeutic targets. Yang J, Zhang L, Qiao W, Luo Y. MedComm (2020) 4 e353 (2023)
  37. Bacterial Enoyl-Reductases: The Ever-Growing List of Fabs, Their Mechanisms and Inhibition. Hopf FSM, Roth CD, de Souza EV, Galina L, Czeczot AM, Machado P, Basso LA, Bizarro CV. Front Microbiol 13 891610 (2022)
  38. Recent advances in the synthesis of new benzothiazole based anti-tubercular compounds. Yadav R, Meena D, Singh K, Tyagi R, Yadav Y, Sagar R. RSC Adv 13 21890-21925 (2023)
  39. [Accidental discoveries, different mechanisms of action. Active agents against Mycobacterium tuberculosis in clinical application]. Weeken D, Schlitzer M. Pharm Unserer Zeit 41 35-47 (2012)

Articles citing this publication (72)



Quick links