Combatting natural resistance and persistence in non-TB mycobacterial disease

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Whereas tuberculosis (TB) lung disease, caused by Mycobacterium tuberculosis is decreasing, lung disease due to a group of close relatives of the tubercle bacillus called `Non-Tuberculous Mycobacteria' or NTM, is increasing. NTM, including M. abscessus and M. avium, infect vulnerable people, such as cystic fibrosis and organ transplant patients, but also the elderly and even apparently healthy young people. NTM are ubiquitous in the environment and intrinsically resistant against most antibiotics. The few antibiotics that work in the test tube do not work well in patients. Treatments usually take years and do often fail. Thus, there is an urgent need to develop new antibiotics to provide a better cure for NTM patients. Here, two experienced TB drug discovery experts, a microbiologist and a pharmacologist, will work together with chemistry colleagues and apply the knowledge they gained over the past decade in the development of TB antibiotics to the discovery of new NTM drugs. NTM can form, similar to M. tuberculosis, non-replicating `persister' bacteria as well as biofilms. These pathophysiological relevant forms of the bacteria are not killed effectively by standard drugs. Furthermore, NTM, like M. tuberculosis tend to be sequestered in lung lesions, granulomata, that are not reached well by our current medicines. The investigators have developed assays that allow the identification of molecules that can reach those hiding places and kill NTM persisters and biofilms. They will not only make use of knowledge and tests developed for TB drug discovery, but also of collections of anti-TB molecules that were generated over the past years in the context of TB discovery projects. They have shown that many molecules that kill M. tuberculosis are also active against NTM. This strategy allows for the efficient generation of chemical starting material for the development of new NTM antibiotics. Three approaches will be followed: 1. Screen collections of anti-TB molecules to identify new anti-NTM molecules. They will then identify the subset of molecules that not only kill growing NTM cells but also the `persister' and biofilm forms, and penetrate the lung lesions in which the bacteria are hiding. For compounds that show these properties, the target will be determined to enable rational, structure- based chemical optimization of the molecules. 2. Improve existing NTM antibiotics. Several antibiotics, such as Linezolid, have been shown to work against NTM but have poor potency. They will screen collections of chemical derivatives of these suboptimal antibiotics to identify molecules that are more potent. 3. Develop a new type of antibiotic that disrupts cell membrane integrity of NTM. They have developed this novel concept for TB bacteria and showed that these novel membrane-targeting molecules are also active against NTM. All three approaches will deliver novel anti-NTM molecules that we will be tested in a mouse model of NTM infection. Together, this project will deliver a series of new anti-NTM lead compounds with proven tolerability, exposure and tolerability in mouse models and known mechanism of action. These molecules can then be subjected to full lead optimizations campaigns to deliver new drug candidates for NTM lung disease.