Antimicrobial resistance (AMR) is a growing public health problem worldwide, that, if left unchecked is predicted by 2050 to annually cause 10 million deaths and cost the world up to 100 trillion USD. Tuberculosis is the bacterial infection most affected by AMR and the estimated global burden of multi-drug resistant tuberculosis is 450,000 each year. The most alarming figure is that extensively drug resistant M. tuberculosis strains have already been reported in more than 92 countries. The increasing burden of multidrug resistant tuberculosis forces us to develop innovative and novel means of killing this organism. The originality of our approach arises from the peculiar observation that a significant number of anti-TB antibiotics are prodrugs, meaning that they acquire their activity thanks to mycobacterial enzymatic bioactivation pathways that are tightly controlled by transcriptional regulators. Using a combination of phenotypic and molecular assays, we have discovered and optimized a new type of antibacterial compounds called SMARt for Small Molecule Aborting Resistance that are able to wake-up a cryptic alternative bio-activation pathway of ethionamide in M. tuberculosis called EthA2, by targeting a transcriptional repressor called EthR2. Treatment of a panel of clinical isolates highly-resistant to ETH because of mutations in ethA were tested by respirometry (MGIT960) with the combination of ETH and SMARt-420. All these strains displayed striking hypersensitivity to ETH with MIC below 0.5 µg/mL. In this experiment, SMARt-420 did not only increase the basal sensitivity of M. tuberculosis to ethionamide but also fully reversed ethionamide-acquired resistance. Finally, mice infected with an ethionamide-resistant mycobacterial strain were also successfully treated orally with the combination of ETH and SMARt-420 (@50mpk) and a 4.6 log reduction of the bacterial load in the lungs was observed.

Teaching old drugs new tricks: Reprogramming ethionamide’s bioactivation to fight multidrug resistant Mycobacterium tuberculosis

253rd National Meeting (2017)

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