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Progress new assets (one pre-new molecular entity and one first-time-in-human start) for tuberculosis that act synergistically with bedaquiline, cytochrome bc or cytochrome bd inhibitors

Periodic Reporting for period 1 - RespiriTB (Progress new assets (one pre-new molecular entity and one first-time-in-human start) for tuberculosis that act synergistically with bedaquiline, cytochrome bc or cytochrome bd inhibitors)

Reporting period: 2019-05-01 to 2020-04-30

Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB), a debilitating disease that causes over 1.5 million deaths each year, more than any other infectious disease such as HIV, malaria, or cholera. The currently available antibiotics against Mtb require a lengthy treatment time of up to nine months and frequently the pathogen develops resistance against the antibiotic. Drug resistant TB requires an even longer treatment of up to 1.5 years with a toxic mix of antibiotics. Therefore, there is an urgent need for novel antibiotics with a shorter treatment time that are less prone to resistance. The RespiriTB projects aims to develop novel antibiotics that target the Mtb respiratory pathway, the energy centre of the bacterium. Treatment will be combined with the recently developed antibiotic bedaquiline that also targets the Mtb respiratory pathway, thus creating a double blow to the bacterium. RespiriTB will also cast a wider net in search for novel antibiotics, by targeting other essential Mtb proteins. In addition, the project will target human factors that are needed for Mtb to survive in the infected host. Our development of novel antibiotics with shorter treatment time and that are less prone to drug resistance will be an essential factor in the fight against TB, the deadliest infectious disease world-wide.
In this project we will perform a high throughput inhibitor screen against selected targets in Mycobacterium tuberculosis. In addition, we will perform a high throughput screen against human factors that are essential for the survival of the bacterium in the human cell. Successful hits will be optimized through medicinal chemistry, while structures of target proteins bound to inhibitor will be determined to aid in this optimization. Lead compounds will be screened for stability, toxicology, pharmacokinetics and dynamics as well as suitable delivery methods. After pre-clinical studies in animal models, First In Human trials will be undertaken as a milestone step towards final development of a novel antibiotic.
This project will develop novel antibiotics against the world's deadliest pathogen M. tuberculosis. It is our aim that these novel antibiotics will have a shorter treatment time and will be less prone to drug resistance than currently used antibiotics. Throughout the duration of the project we will identify novel bacterial and host factors that can be targeted to cure infections by M. tuberculosis. We will also determine structures of these targets with inhibitors bound, and where necessary determine the mode of action of these targets. Given the millions of deaths each year caused by M. tuberculosis, as well as the many more debilitating infections, the potential impacts of this project are vast, as it will improve the prognosis of millions TB patients world-wide.