Discovery of novel inhibitors targeting the mycobacterial cell wall

Résumé

The challenge of antibiotic resistant bacterial pathogens has urged the scientific community to develop new therapeutic approaches. An old but efficient strategy consisting in targeting the cell wall biosynthesis remains powerful.
Twenty years after the WHO declared TB disease to be a global public health emergency, limited progress has been made on curbing, let alone eradicating, the TB epidemic. In 2015, there were an estimated 10.4 million incident cases of tuberculosis (TB), and an estimated of TB incidence have been revised upwards for the period 2000–2015. In an attempt to combat the global TB epidemic, there has been extensive research into the development of novel vaccines and chemotherapeutics against TB. With the emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB, leading the current drugs lose efficiency. Therefore the desperate need for antibiotics with novel mechanisms of action remains.
Among the different enzymes involved in the formation of the mycobacterial cell wall, UDP-Galactopyranose mutase (UGM) was identified as a new target. Indeed, this enzyme allows a peculiar reaction: the contraction of the cycle of UDP-Galp into UDP-Galf.
This thesis was based on the identification of novel potential inhibitors of UGM in order to understand the mechanism of this enzyme. The enzymatic studies were performed on two different categories of molecules: synthetic compounds and natural products.
In the first part of this project, dynamic combinatorial chemistry (DCC) and in situ screening were successfully applied to identify drug-like small molecule inhibors of UGM. Rewardingly, the best enzyme ligands also displayed activities against an attenuated strain of M. tuberculosis. In addition, a series of enamides were identified via combinatorial in situ screening as a new class of antimycobacterial agents. The most potent UGM inhibitor exhibited antimycobacterial activity in vitro against M. bovis, and this is the first time we have been able to observe the link between UGM inhibition and M. bovis growth inhibition.
The second part reported the screening of a small library of natural products which lead to identify new potential inhibitors of UGM. Among them, luteolin emerged as a potent lead compound, served as good starting pointing for further design.
In the last section of this thesis, we described the overxepression of NagZ from E coli, an important enzyme that triggers AmpC regulation in Gram-negative bacteria which is linked to antibiotic resistance. We also carried out an extensive inhibition study on a library of mechanistic-based molecules, natural products and synthetic derivatives.

la date de réponse	oct. 2017
langue originale	Anglais
L'institution diplômante	Universite de Namur
Sponsors	China Scholarship Council
Superviseur	Stephane Vincent (Promoteur), Yongmin Zhang (Jury), R Daniellou (Jury), Steve Lanners (Jury) & Weidong Pan (Jury)