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JPIAMR-JPI Antimikrobiell resistens

New intervention strategy for tuberculosis: blocking multiple essential targets

Awarded: NOK 5.4 mill.

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a disease responsible for almost 1.5 million deaths per year. In recent years, different classes of drug resistant Mtb strains have emerged, making the discovery of novel anti-TB drugs a major global priority. This awareness has resulted in several new initiatives to find new (classes of) antimicrobial compounds. A major disadvantage of most existing and emerging TB drugs is that they target a single molecule, which significantly increases the probability that resistant strains will emerge. In this project, we will address this problem by identifying compounds that target multiple type VII secretion systems (T7SS) in Mtb. Mtb has five of these T7SS, three of which are essential for virulence in the pathogen: Esx-1, Esx-3 and Esx-5. In the project consortium, we have partners with expertise on these three essential T7SS. Our group has a focus on Esx-3, while other partners in the consortium focus on Esx-1 and Esx-5. Since the start of the project in January 2015 we hired one post doc and in May 2015 we hired one engineer for the project. We have established a biosafety level 3 (BSL3) laboratory at NTNU. This has been essential for the further progress of the project and the lab will be very important for the further development of our research on infectious diseases. Due to delays in getting the BSL3 lab established we have been delayed in developing assays necessary for the screening of potential T7SS Esx-3 drug candidates, but we started the development of a colorimetric assay that will detect Esx-3 secretion substrates using various detection techniques. The screen is almost ready and we will screen for anti-tuberculosis compounds in 2018. The project will hopefully be prolonged for 6 months to enable us to fulfill the proposed milestones of the project. As part of the tool development we also constructed a protein expression system to be used in Mtb and we published this in PLOS One (2015, Dragset et al.). 2015-2017 other partners in the consortium have been active and screens for both Esx-1 and Esx-5 have been developed. The screen for compounds active against these two systems has been finalized in 2016 and early 2017 and the further characterization of the active compunds have been continued throughout 2017. We have had three consortium meetings (Amsterdam, Paris and Trondheim) to present results and exchange methodology. The last meeting was in Trondheim early 2017. The results from our assay development have been presented at three international conferences in 2016 (the Keystone symposium "Tuberculosis co-morbidities and immunopathogenesis" in Keystone, Colorado, USA, the Conference on Molecular Mechanisms of Inflammation in Trondheim, Norway and the EMBO conference "Tuberculosis 2016: Interdisciplinary research on tuberculosis and pathogenic mycobacteria" in Paris, France). The focus on antimicrobial resistance has created some media interest and Steigedal has featured in interviews regarding this. Steigedal also presented the work in this project at the NRK popular science show "Schrødingers katt". For late 2017 and so far in 2018 we have had one consortium meeting in Paris. There we exchanged data and planned the final stages of the project. As a result we now have tested the compounds identified that prevents secretion from ESX-5 for ability to prevent secretion from ESX-3. We are currently trying to identify the specific targets of such compounds, and will investigate the role of the compounds in killing the bacterium. We expect to publish papers from the project in collaboration with consortium partners.

Mycobacterium tuberculosisis the causative agent of tuberculosis (TB), a disease responsible for almost 1.3 million deaths per year. In recent years, different classes of drug resistant M. tuberculosis strains have emerged, making the discovery of novel anti-TB drugs a major global priority. A major disadvantage of most existing and new TB compounds is that they target a single molecule, which significantly increases the chance that resistant strains will emerge. In this project, we will address this problem by identifying compounds that target multiple type VII secretion (T7S) systems. T7S systems are used by M. tuberculosis to secrete proteins across the cell envelope to the cell surface or into the host environment. Interestingly, this bacterium has several different T7S systems, three of which are essential for viability or virulence. We predict that, by blocking multiple T7S systems with a single compound, we will considerably reduce the development of drug resistance. As proof of principle, we have already successfully used the first approach to identify two different classes of compounds that block T7S systems. Importantly, one of these compounds significantly reduced mycobacterial growth in vivo. For the second approach we will exploit the detailed knowledge of T7S systems that has been recently generated within the consortium, including structures of several crucial druggable components. To increase the activities of our secretion-blocking compounds, we will also identify compounds that act synergistically with them from libraries of antibiotics and other FDA-approved drugs. Subsequently (combinations of) compounds will be tested in vivo in a high throughput animal model for activity, toxicity and resistance development to study the concept that by inactivating multiple essential targets, the emergence of drug resistance is reduced.

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JPIAMR-JPI Antimikrobiell resistens