Projet de recherche BL/11/IN20 (Action de recherche BL)
Project objectives: Development of vancomycin analogues to kill, alone or in combination, multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis in order to cure patients with MDR tuberculosis.
Aim 1: Concept, synthesis, purification and characterization of vancomycin analogues
Aim 2: Biological activity evaluation of vancomycin analogues against Mycobacteria
Aim 3: Investigating mammalian cell toxicity of vancomycin analogues
Aim 4: Investigating detailed mechanism of action against Mycobacteria
The complementary skills and expertise of the network members will ensure successful completion of the objectives.
National and international relevance/novelty: Mycobacterium tuberculosis is the second infectious agent, after SARS-CoV-2, responsible of death in the world). Globally, ten millions new tuberculosis patients are estimated every years and 25% of them are living in India. Vulnerable populations, with a high immigrant rate, indeed have higher TB incidence. In 2018, the incidence rate was 4.8 times higher in the Brussels-Capital region than in Wallonia and Flanders (FARES/ VRGT), but not commensurate with the incidence rate in India (193/100.000). The treatment of this pathology is long (6 months) and complicated (minimum 4 anti-tuberculosis drugs). This often leads to the emergence of multidrug resistant (MDR) or extremely resistant (XDR) strains. In 2019, there were 500,000 tuberculosis caused by MDR strains and 27% were present in India. Those MDR and XDR strains are a real threat requiring urgent new anti-TB drug development. The Belgian team patented a combination of vancomycin with tetrahydrolipstatin (THL or Orlistat) able to target MDR and XDR M. tuberculosis clinical isolates, while the Indian team got expertise in vancomycin analogues synthesis.
Specific R&D cooperation topic: the Belgian team discovered and patented a combination vancomycin with Orlistat to inhibit MDR and XDR M. tuberculosis, that should be improved. The Indian group has developed various vancomycin analogues, which have been patented. They showed activity against vancomycin-resistant Gram-positive and Gram-negative bacteria. Many of these derivatives will be tested against Mycobacteria through this project. Indeed, vancomycin is poorly active inside infected macrophage. The combination of new vancomycin analogues and tetrahydrolipstatin (THL) will be tested for their antimycobacterial activity. This network aims thus to develop vancomycin analogues able to cross cellular membranes.
Expected results of the network: The expert exchanges will lead to generation of new data on the antimycobacterial activity of vancomycin analogues. The jointly generated data will be published in peer-reviewed international journals. During the course of the project, PhD students, research assistants and associates will be trained in various techniques. The collaborative work will lead to the development of at least one new therapeutic regimen for Mycobacteria with identified mechanisms of action.
