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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 2 - 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: 2020-05-01 to 2021-04-30

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.
It is the aim of the RespiriTB project to develop novel inhibitors of Mycobacterium tuberculosis that will shorten the treatment time and reduce the rate of antibiotic resistance. In our project we employ three approaches in parallel. The first approach is to inhibit the energy center of the bacterium thus depleting it from the energy it needs to survive. For this we focus on two essential elements of the energy center, cytochrome bc and cytochrome bd complexes. The second approach of the RespiriTB project is to target the mycothione reductase protein that neutralizes harmful reactive oxygen species that arise naturally in the life of a cell. Thus, by inhibiting the mycothione reductase we pollute the bacterium and create toxic conditions that will kill the bacterium. Finally, our third approach is different from the first two approaches as instead of targeting the bacterium directly, it targets the environment that it needs to survive. As M. tuberculosis resides inside of a human cell, it has evolved to manipulate the host to create a beneficial environment for it to proliferate in. By interfering with the bacterium's manipulation of the human cell, we will create a hostile environment in which the bacterium cannot survive. This 'host-directed therapy' has the major advantage that the inhibitors are aimed human targets, for which the bacterium has no means to generate resistance to.
Results 1 - cytochromes. We have progressed one of the selected cytochrome inhibitors through pre-clinical studies to prepare it for Phase-I clinical trials. In addition, we have extracted and purified the cytochrome bc and cytochrome bd complexes to study their interaction with the inhibitors using biochemical and structural methods. This way we will be able to improve the potency of the inhibitors as well as study drug resistance inducing mutations in order to create novel inhibitor versions that are less susceptible to resistance inducing mutations.
Results 2 - Mycothione reductase. Since the beginning of the project, we extracted and purified the mycothione reductase protein and used it to identify novel inhibitors. These novel inhibitors are currently being evaluated so that a small set of these can be selected to enter the drug development pipeline. The mycothione reductase protein will also be used for structural studies to improve our understanding of inhibitor binding and increase their potency and selectivity.
Results 3 - host directed therapies. We have created a small set of host-directed inhibitors that reduce the growth of the bacterium within the human cell. These compounds are currently evaluated further to create a smaller selection that will enter the drug development pipeline.
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.
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