Comprehensive host cell-based drug discovery targeting innate immunity, virulence and essential functions of Mycobacterium tuberculosis

点击翻译按钮获取中文摘要

The emergence of multidrug resistant bacteria is a major public health concern with increased morbidity and mortality throughout the world. In addition to the search for novel antibiotics, alternative approaches, such as the development of anti-virulence drugs and adjunctive host directed therapies are necessary to fill the antibiotic gap that appeared in the past decade. We have developed a drug screening platform for the major human pathogen Mycobacterium tuberculosis (Mtb) that is capable of combining all three approaches in a single assay. Control of the current tuberculosis (TB) pandemic is threatened due to increasing multidrug resistance and the lack of novel substances active against this pathogen. Our comprehensive drug screening approach is based on virulence factor driven host cell-lysis. Proof of concept studies identified novel Mtb-specific antibiotics as well as anti-virulence drugs targeting the ESX-1 secretion system, a major mycobacterial virulence factor. We also found widely used corticosteroids to be highly protective for ESX-1 induced cytotoxicity. This is an intriguing finding since corticosteroids represent the only clinically approved adjunctive host-directed therapy for TB-treatment; however, their mechanism of action in active TB is unknown. Our assay provides the unique opportunity to study mechanisms of Mtb induced cytotoxicity and how corticosteroids interfere with these in favor of the host-cell. A second major aim of this proposal is the identification of novel antibiotics and anti-virulance drugs as well as drugs with corticosteroid-like behavior using the well-established cell survival assay and a library of more than 40,000 small molecules. Hit compounds will provide leads for new treatment options against multi-drug resistant Mtb. In addition, novel immunomodulatory agents can be identified that may find applications in other disease backgrounds such as autoimmune diseases or cancer. Our data will provide insight into pathogen-driven cytotoxicity and innate immunity counter measures with a strong focus on therapeutic interventions.