DEVELOPING INNOVATIVE STRATEGIES IN THE FIGHT AGAINST ANTIBIOTIC RESISTANCE
SMARt
CONTEXT
Tuberculosis (TB) is still a scourge of mankind. TB treatment regimen relies on old first line drugs. Poor patient adherence leads to the repeated exposure of the bacterium to sub-inhibitory drug concentrations that select for resistance. As a result, multiple drug-resistant TB (MDR-TB) strains have now emerged. Recent efforts have led to the identification of new promising drugs, including the bedaquiline and delamanid, but the anti-TB drug pipeline remains insufficiently filled.
TB proDRUGS & BIOACTIVATION
Many antituberculosis drugs are pro-antibiotics (or prodrugs), which means they require bioactivation to exhibit their antibacterial activity. Singularly, all pro-antibiotics known today are in fact antituberculosis compounds, with the exception of metronidazole which has a larger spectrum of activity. Their transformation is catalyzed by drug-specific mycobacterial enzymes. For example, pyrazinamide (PZA) is activated by the pyrazinamidase PncA and isoniazid (INH) by the catalase peroxidase KatG. Bioactivations of Pretomanid and Delamanid, involve the deazaflavin-dependent nitroreductase (ddn) and the monooxygenase EthA bioactivates ethionamide (ETH), thiacetazone (TAZ) and isoxyl (ISO).
SMARt STRATEGY
Bioactivation of the second-line drug ethionamide (ETH) is performed inside Mycobacterium tuberculosis by the monooxygenase EthA.
Transcription of ethA is under the control of the transcription factor EthR. In 2009, we identified and optimized EthR inhibitors to stimulate the production of EthA and thus ETH bioactivation. Results demonstrated that our lead compound was able to triple the activity of ETH in a TB-infected mice model.
During our Medicinal Chemistry program, we identified compounds able to derepress a cryptic bioactivation pathway that we proved able to bioactivate ethionamide independently of EthA.
We have now demonstrated that our SMARt molecules (Small Molecules Aborting Resistance) inhibit a new transcription factor called EthR2, releasing the production of a new oxydoreductase called EthA2. the combination of ETH and the lead compound SMARt-420 was shown highly active against all TB strains tested so far, including MDR strains mutated in EthA.
CONTACT US
Institut Pasteur de Lille