Ethionamide: A “new” first-line drug for Tuberculosis?

3 Mar 2010
by Working Group

Detailed view of the ligand-binding site of EthR co-crystallized with BDM31381 (EthRInhibitor)
Detailed view of the ligand-binding site of EthR co-crystallized with BDM31381 (EthRInhibitor)

Developing new TB drugs is inhibited by so many factors – namely:

  1. The flow through the TB drug pipeline is slow at best. Despite decades of hard work, we still use the demanding regimen developed 50 years ago – a regimen that requires patients to undergo 6-9 months of treatment consisting of four first-line TB drugs.
  2. This lengthy course often results in non-compliance, which has provoked new drug resistant strains of TB (MDR-TB and XDR-TB). MDR-TB is now estimated to comprise up to 5% of all new TB cases and requires therapy for nearly two years with second-line TB drugs. These drugs are not only more expensive, but there are also adverse side effects, such as nausea , because of the high dosage needed.
  3. We really need new TB drugs because of XDR-TB, which is resistant to almost all of the highly effective second-line TB drugs. Although promising anti-mycobacterial compounds have been identified, it will be years before they are developed. Further, only 10% of antibiotics that enter early clinical trials are approved.

Which gets me to my point: Instead of focusing all our energy on new drugs, why not improve the drugs we already have? This is what Alain Baulard and his colleagues at the Pasteur Institute in Lille, France, have done with the second-line TB drug, ethionamide.

Like many antituberculosis compounds, ethionamide requires metabolic activation before it is able to kill bacteria. The drug is activated by a bacterial enzyme, EthA, and the production of EthA is in turn inhibited by the transcriptional repressor, EthR. To address the possibility of boosting the antituberculous activity of ethionamide, Baulard and his colleagues set out to identify compounds that would inhibit EthR, subsequently increasing the metabolic activation and efficacy of ethionamide. To identify these inhibitors, they developed a chemical screen to look for compounds that were able to disrupt the interaction of EthR with DNA. These compounds were co-crystallized with EthR and, by making use of the complex’s three-dimensional structure, analogs were synthesized and optimized for their ability to boost ethionamide potency. These compounds were able to increase the potency of ethionamide by almost tenfold in culture. When tested in Mycobacterium tuberculosis infected mice, addition of the EthR inhibitor reduced the amount of ethionamide required to decrease bacterial load threefold compared to using the drug alone.

High doses of ethionamide have side effects that limit its use and thus relegate it to a second-line TB drug. Addition of the ethionamide “booster” means a much smaller dose can be administered with equal efficacy and substantially decreased toxicity compared to the conventional high dose.

The work by Boulard also highlights a new avenue for drug research in development of compounds that increase efficacy of existing antimycobacterial drugs and limit their side effects. Although many questions still remain with regards to the feasibility of introducing a “booster” drug to the already heavy TB drug regimen, as well as increasing the use of ethionamide when XDR-TB is on the rise, the question is worth posing:

“Could ethionamide now be reconsidered as a first-line TB drug?”

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