EC Clinical and Medical Case Reports

Review Article Volume 7 Issue 2 - 2024

Unraveling the EthR Puzzle: Exploring Novel Inhibitors in the Fight against Tuberculosis from a Medicinal Chemistry Vistas

Harshali Chonde1, Vinayak Walhekar1, Mahak Jat1, Ashwini Patil1, Mangala Khandekar2, Aasiya Chaudhary2, Vibhav Shinde3, Amol Muthal4 and Ravindra G Kulkarni1*

1Department of Pharmaceutical Chemistry, BVDU’s Poona College of Pharmacy, Erandwane, Pune, Maharashtra, India

2Department of Pharmaceutical Chemistry, SVERIs College of Pharmacy, Gopalpur, Pandharpur, Maharashtra, India

3Department of Pharmacognosy, BVDU’s Poona College of Pharmacy, Erandwane, Pune, Maharashtra, India

4Department of Pharmacology, BVDU’s Poona College of Pharmacy, Erandwane, Pune, Maharashtra, India

*Corresponding Author: Ravindra G Kulkarni, Professor, Head of Department, Department of Pharmaceutical Chemistry, BVDU’s Poona College of Pharmacy, Erandwane, Pune, Maharashtra, India.
Received: October 31, 2023; Published: January 30, 2024



Tuberculosis stands as a menacing infectious disease that has instilled worldwide apprehension owing to its profound impact on the well-being of afflicted individuals. Ethionamide is the second line drug therapy for active multidrug resistant tuberculosis. Functional impairment of EthA enzyme which is responsible for the activation of ETH (Ethionamide) result in drug resistance in Mtb. To combat against Ethionamide resistance and boost up its activity against Mtb in second line therapy of tuberculosis, various types of ETH boosters have been designed and/or developed by different strategies. These Ethionamide promoters work by upregulating the action of EthA enzyme. The gene responsible for downregulation of EthA enzyme is EthR gene and the process is called as ETH repression which is the cause of drug resistance. So, to get prevail over this Ethionamide resistance and to enhance ETH activation in Mtb infected cell, EthR inhibitors are designed and developed to upregulate the EthA enzyme. EthR inhibitors demonstrated the desired interaction into its DNA recognition site that results into inhibition of EthR activation.

 Keywords: Ethionamide repressor (EthR); Ethionamide (ETH); Ethionamide activator; Mycobacterium tuberculosis (Mtb)

  1. Turgenbayev KA., et al. "Tuberculosis prevalence in animals and humans in the Republic of Kazakhstan”. Veterinary World9 (2021): 2362-2370.
  2. DeBarber Andrea E., et al. "Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis”. Proceedings of the National Academy of Sciences17 (2000): 9677-9682.
  3. Engohang‐Ndong Jean., et al. "EthR, a repressor of the TetR/CamR family implicated in ethionamide resistance in mycobacteria, octamerizes cooperatively on its operator”. Molecular Microbiology1 (2004): 175-188.
  4. Sawicki Rafal and Grazyna Ginalska. "Mycobacterium tuberculosis topoisomerases and EthR as the targets for new anti-TB drugs development”. Future Medicinal Chemistry16 (2019): 2193-2203.
  5. Willand Nicolas., et al. "Recent advances in the design of inhibitors of mycobacterial regulators to boost thioamides anti-tubercular activity and circumvent acquired-resistance”. Annual transcriptional Reports in Medicinal Chemistry 52 (2019): 131-152.
  6. Vannelli Tommaso A., et al. "The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase”. Journal of Biological Chemistry15 (2002): 12824-12829.
  7. Fraaije Marco W., et al. "The prodrug activator EtaA from Mycobacterium tuberculosis is a Baeyer-Villiger monooxygenase”. Journal of Biological Chemistry5 (2004): 3354-3360.
  8. Wang Feng., et al. "Mechanism of thioamide drug action against tuberculosis and leprosy”. The Journal of Experimental Medicine1 (2007): 73-78.
  9. Dover Lynn G., et al. "Crystal structure of the TetR/CamR family repressor Mycobacterium tuberculosis EthR implicated in ethionamide resistance”. Journal of Molecular Biology5 (2004): 1095-1105.
  10. Schumacher Maria A., et al. "Structural mechanisms of QacR induction and multidrug recognition”. Science5549 (2001): 2158-2163.
  11. Frénois Frédéric., et al. "Structure of EthR in a ligand bound conformation reveals therapeutic perspectives against tuberculosis”. Molecular Cell2 (2004): 301-307.
  12. Vilchèze Catherine., et al. "Transfer of a point mutation in Mycobacterium tuberculosis inhA resolves the target of isoniazid”. Nature Medicine9 (2006): 1027-1029.
  13. Vilcheze Catherine., et al. "Altered NADH/NAD+ ratio mediates coresistance to isoniazid and ethionamide in mycobacteria”. Antimicrobial Agents and Chemotherapy2 (2005): 708-720.
  14. Grau Thomas., et al. "Phenylethyl butyrate enhances the potency of second-line drugs against clinical isolates of Mycobacterium tuberculosis”. Antimicrobial Agents and Chemotherapy2 (2012): 1142-1145.
  15. Prevet Hugues., et al. "A fragment-based approach towards the discovery of N-substituted tropinones as inhibitors of Mycobacterium tuberculosis transcriptional regulator EthR2”. European Journal of Medicinal Chemistry 167 (2019): 426-438.
  16. Villemagne Baptiste., et al. "Fragment-based optimized EthR inhibitors with in vivo ethionamide boosting activity”. ACS Infectious Diseases3 (2020): 366-378.
  17. Nikiforov Petar O., et al. "Fragment-sized EthR inhibitors exhibit exceptionally strong ethionamide boosting effect in whole-cell Mycobacterium tuberculosis assays”. ACS Chemical Biology5 (2017): 1390-1396.
  18. Nikiforov Petar O., et al. "A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters”. Organic and Biomolecular Chemistry7 (2016): 2318-2326.
  19. Blondiaux Nicolas., et al. "Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420”. Science6330 (2017): 1206-1211.
  20. Willand Nicolas, et al. "Synthetic EthR inhibitors boost antituberculous activity of ethionamide”. Nature Medicine5 (2009): 537-544.
  21. Flipo Marion., et al. "Ethionamide boosters. 2. Combining bioisosteric replacement and structure-based drug design to solve pharmacokinetic issues in a series of potent 1, 2, 4-oxadiazole EthR inhibitors”. Journal of Medicinal Chemistry1 (2012): 68-83.
  22. Tatum Natalie J., et al. "Structural and docking studies of potent ethionamide boosters”. Acta Crystallographica Section C: Crystal Structure Communications11 (2013): 1243-1250.
  23. Halder Sajal Kumar and Fatiha Elma. "In silico identification of novel chemical compounds with antituberculosis activity for the inhibition of InhA and EthR proteins from Mycobacterium tuberculosis”. Journal of Clinical Tuberculosis and Other Mycobacterial Diseases 24 (2021): 100246.

Ravindra G Kulkarni., et al. "Unraveling the EthR Puzzle: Exploring Novel Inhibitors in the Fight against Tuberculosis from a Medicinal Chemistry Vistas." EC Clinical and Medical Case Reports   7.2 (2024): 01-14.