SMARt-TB : Identification of Small Molecules Aborting Resistance to TB prodrugs

During the last few years, our research-consortium has developed an alternative strategy to revert resistance to antibiotics. We have demonstrated that resistance of M. tb to the prodrug ethionamide can be circumvented by waking up alternative bioactivation pathways using small molecules. Buoyed by this initial success, we have now extended this innovative concept to tackle resistance associated to the two nitroimidazoles: pretomanid and delamanid.

We have identified small molecules (SMARt -Nim) that boost the activity of pretomanid and delamanid. The goals of this project is to unravel their mode of action and to optimize their properties.

Using an innovative screening approach, we have identified Small-Molecules Aborting Resistance (SMARt) to the two nitroimidazoles prodrugs: pretomanid and delamanid. The first goals of this project is to unravel the mode of action of these compounds. The second goal will be to study the proteins that restore, directly or indirectly the sensitivity of the bacteria to the prodrugs, which includes deciphering the mechanisms of bioactivation of the prodrugs upon treatment with SMARt-PRE compounds. Escape mechanisms will be studied, not only to understand the mode of action but also to predict the frequency and the mechanism of resistance in the prospect of clinical applications. This work will be done using state-of-the-art biology and biochemistry techniques. The third objective of this project will be to improve the pharmacodynamics and pharmacokinetic properties of the chemical series in order to perform an in vivo proof of concept.