Journal of Organic & Inorganic Chemistry

Teaching old drugs new tricks: reprogramming thioamide’s bioactivation to fight multidrug resistant Mycobacterium tuberculosis

EuroSciCon Conference on Chemistry 2018
February 19-20, 2018 Paris, France

Nicolas Willand, Marc Gitzinger, Benoit Deprez and Alain Baulard

P Lille University, France BioVersys AG, Switzerland

Posters & Accepted Abstracts: J Org Inorg Chem

DOI: 10.21767/2472-1123-C1-003

Abstract

Antimicrobial resistance (AMR) is a growing public health problem worldwide and tuberculosis is the bacterial infection most affected by AMR. The estimated global burden of multi-drug resistant tuberculosis is 450,000 each year. The most alarming figure is that extensively drug resistant Mycobacterium tuberculosis (M. tuberculosis) (XDRMtb) has already been reported in more than 92 countries, which forces us to develop innovative approaches to revert resistance. The originality of our approach arises from the peculiar observation that a significant number of anti-TB antibiotics are prodrugs, meaning that they become active inside of the mycobacteria thanks to specific mycobacterial enzymatic bioactivations, tightly controlled by transcriptional regulators. Ethionamide (ETH), for instance, requires intracellular activation by a monooxygenase called EthA. EthR, a transcriptional repressor (TR), controls the expression of EthA and thus limits ETH conversion into its active form. Use of EthR inhibitors in combination with ETH showed a strong effect in boosting EthA production and thus sensitivity to the prodrug. Using a combination of phenotypic and molecular assays, we have discovered and optimized a new type of compounds called SMARt (Small Molecule Aborting Resistance) that are now able to wake-up cryptic bio-activation pathways of ethionamide, and consequently revert resistance to the prodrug. Treatment of a large panel of clinical isolates highly resistant to ETH with the combination of SMARt-420 and ETH, allowed inhibiting growth with MIC below the resistant threshold of 0.5 �?¼g/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 ( 50 mpk) and a 4.6 log reduction of the bacterial load in the lunâ�?�?gs was observed. From our last generation of SMARt molecules, we have now been able to select a preclinical candidate. nicolas.willand@univ-lille2.fr