Identification and characterization of anti-tuberculosis compounds to activate endogenous suicide toxin
Among all infectious diseases, tuberculosis is the top cause of death due to a single infectious agent, Mycobacterium tuberculosis, with 10.4 million cases and 1.7 million deaths in 2016. Effective treatment of tuberculosis requires a combination of four front-line antibiotics taken for a minimum of six months. The rise of new strains of Mycobacterium tuberculosis resistant to drug treatment, often combined with viral co-infections such as HIV, has been recognized as one of the gravest public health threats facing the world today. Multidrug-resistant Mycobacterium tuberculosis strains tolerate at least of the two leading tuberculosis drugs, but resistance to second line drugs (extensively drug resistant) or to all major drugs (totally drug resistant) is also emerging rapidly. Since 2015, this effect has been accelerated in European countries and the Near East due to the large numbers of refugees from war zones in the Middle East. New innovative approaches to tuberculosis drug development are urgently needed.
A novel bactericidal toxin called MbcT from Mycobacterium tuberculosis will be exploited to design a novel antituberculosis therapeutic strategy. MbcT has the unpreceded ability to degrade the essential cellular metabolite nicotinamide adenine dinucleotide (NAD). The aim is to trigger the disassembly of the toxin from its native inactivating protein antidote MbcA using small molecule interference, guided by the structural details of the toxin/antitoxin interface and in vivo functional data. The goal of the project is to identify and characterize promising compounds with high efficacy for MbcT toxin activation by combining a structure-based in silico screening approach and in vitro high-throughput screening, followed by several validation steps. The results of the project will allow defining subsequent activities, and evaluation of the usefulness of the MbcTA system as a model for related toxin/antitoxin systems in other bacterial pathogens.
PI: Prof Dr Matthias Wilmanns - EMBL European Molecular Biology Laboratory, Hamburg
First broad spectrum small molecule inhibitors against polyomaviruses
Human polyomaviruses (HPyV) are highly abundant in the human population. Primary infection usually occurs in childhood and is followed by lifelong persistence. While these chronic infections are usually indolent in immunocompetent individuals, polyomaviruses can induce severe and life‐threatening disease in the elderly and the immunosuppressed. Considering the increasing age of the general population, it is to be expected that the frequency of these viral diseases will continue to increase. In the last ten years, the family of human polyomaviruses has expanded from two to 13 known members; of these, Merkel cell polyomavirus (MCPyV), Trichodisplasia spinulosa virus (TSPyV) and in particular, BK‐Virus (BKV) as well as the closely related JC‐Virus (JCV) are of clinical importance. JCV and BKV reactivation is a fundamental concern in immunosuppressed patients. Indeed, uncontrolled BKV replication occurs in up to 75% of the risk groups and results in haemorrhagic cystitis in 5 – 15% of allogenic transplant patients, whereas up to 20% of kidney transplant patients suffer from polyomavirus‐associated nephropathy (PVAN) and subsequent graft loss. JCV reactivation/infection in immunosuppressed patients can result in a potentially fatal disorder, progressive multifocal leukoencephalopathy (PML) with highest incidence in multiple sclerosis (MS) patients (drug‐induced PML) with 0.33‐1/100 patients. Remarkably, despite the fact that BKV and JCV have been recognized as important human pathogens for more than 50 years, to date no specific antiviral therapies are available to treat PyV‐associated diseases.
To alleviate the urgent need for such therapies, a high‐throughput screen for small molecule inhibitors of BKV was performed with nine BK‐Virus specific inhibitors identified. Initial evaluation of pharmacokinetics, MedChem friendliness, IC50 calculation together with multiparameter cytotoxicity assays identified two inhibitors that satisfy selectivity index criteria and exhibit efficacy in the lower μM range. To further advance the development of effective anti‐PyV drugs, the project aims for structure activity relation (SAR), target deconvolution and first in vitro drug metabolism and pharmacokinetics studies.
PI: Prof Dr Nicole Fischer - University Medical Center Hamburg‐Eppendorf
Co: Prof Dr Adam Grundhoff - Heinrich‐Pette Institute, Leibniz Institute for Experimental Virology