In the past decade, we have seen a dramatic increase worldwide in the number of antibiotic-resistant bacteria, against which the effective therapeutic arsenal is gradually disappearing. Tuberculosis is particularly concerned by the emergence of multidrug-resistant strains. These resistances very often force doctors to prolong the treatment and to adapt the antibiotic cocktail used during treatment, which further delays or even precludes healing. In addition, while strains resistant to all antibiotics are exceptional, they raise concerns of a future TB epidemic with restricted therapeutic options. There is therefore a real medical need for new therapeutic approaches to fight more effectively against resistance. The treatment of tuberculosis is based on the use of a large number of pro-antibiotics including pyrazinamide (PZA), delamanid, and maybe soon pretomanid, which have the particularity of being active against dormant bacilli. Nevertheless, the future of PZA is seriously compromised by the high rate of circulating resistant strains, and resistance to the nitro-imidazoles pretomanid and delamanid is already documented, even though these molecules are still under clinical evaluation.
The SMARt-TB project propose a new way of fighting resistance to PZA and to nitro-imidazoles in tuberculosis, a concept we recently proved possible with SMARt compounds reverting resistance to ethionamide. We have now used an innovative phenotypic screening involving bacteria resistant to PZA and to nitro-imidazoles, and we have identified small molecules called SMARtPZA and SMARtPRE (Small Molecules Aborting Resistance) that allow to revert resistance to these antibiotics. Transcriptomic experiments already allow us to infer the mode of action of SMARtPRE hits, which obviously stimulate an alternative bioactivation pathway of nitro-imidazoles.
The main objectives of the SMARt-TB project are (1) to synthetize highly efficient analogs of the SMARt hits identified by screening, (2) to characterize the molecular basis of the mode of action of our SMARt molecules, (3) to identify the bioactivation process of the pro-antibiotics through the new awakened pathways, (4) to develop "drug-like" lead-molecules to evaluate the therapeutic potential in mouse models infected with PZA- or nitroimidazole- resistant TB strains. Our objectives after 42 months are therefore to identify and validate new bioactivation pathways of PZA and pretomanid, and to allow the development of combinations of drug-like molecules to revert resistance to these two major anti-tuberculosis drugs.
If SMARt-TB confirms further the potential of reprogramming mycobacteria to bio-activate essential prodrugs, this strategy may progressively lead to a new era where resistance can be reverted, and maybe prevented.
Monsieur Nicolas Willand (INSTITUT PASTEUR DE LILLE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IPL - U1177 INSTITUT PASTEUR DE LILLE
Unité de glycobiologie structurale et fonctionnelle
IPL - CIIL INSTITUT PASTEUR DE LILLE
Help of the ANR 510,868 euros
Beginning and duration of the scientific project: October 2018 - 42 Months