Coordinators:
- INSERM U629 : Alain Baulard
- INSERM U761 : Nicolas Willand
Mission:
With one third of the world population infected, more than 9 million people developing the active disease and 2 million deaths each year, Tuberculosis (TB) remains a worldwide health threat.1 Attempts to treat TB are hindered by the increasing spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis leading to less effective and more toxic drugs, longer periods of treatment and a decreasing compliance of the therapy.
Objectives and rationale:
Current tuberculosis therapies include a large number of prodrugs that must be metabolically activated to manifest their activity. This is the case for ethionamide (ETH) that requires activation by the mycobacterial monooxygenase EthA to be effective. This phenomenon is limited by the mycobacterial transcriptional regulator EthR and we recently showed that appropriate inhibitors of EthR can enhance M. tuberculosis sensitivity to ETH in vitro and in vivo.2 As ETH, isoniazid (INH) is also a prodrug whose bioactivation is provided by the mycobacterial catalase-peroxidase KatG.3 KatG expression is down-regulated by FurA, a ferric uptake regulator and several groups showed that inactivation of furA resulted in derepression of KatG leading to an increased sentivity of Mycobacterium tuberculosis to INH.3 Our strategy relies on the development of FurA inhibitors in order to boost INH bioactivation in vivo. We will be able to lower doses and minimize side effects, making the therapeutic regimen more efficient, improving compliance and finally reducing the occurrence of resistant strains of mycobacteria. Since no crystallographic data were available at the start of the project, we developed an in vitro high-throughput fluorescence-based thermal shift assay (TSA) to screen our library of drug-like molecules (45 000) and find Hit molecules. In parallel a functional assay was developed and used to confirm hits activities. We are no currently optimizing pharmacodynamic and pharmacokinetic properties of identified chemotypes in order to validate this original approach in vivo.
References
1 Global tuberculosis control: epidemiology, strategy, financing: WHO report 2009, WHO/HTM/TB/2009.411. 2 Synthetic EthR inhibitors boost antituberculous activity of ethionamide Willand N , Dirié B, Carette X, Bifani P, Singhal A, Desroses M, Leroux F, Willery E, Mathys V, Déprez-Poulain R, Delcroix G, Frénois F, Aumercier M, Locht C, Villeret V, Déprez B, Baulard AR Nature Medicine 2009, 15, 537-544. 3 Regulation of catalase-peroxidase (KatG) expression, isoniazid sensitivity and virulence by FurA of Mycobacterium tuberculosis Molecular Microbiology Pym A, Domenech P, Honoré N, Deretic V, Cole S 2001, 40, 879-889.
