| Zusammenfassung |
Tuberculosis (TB) is one of the leading causes of death worldwide from a single infectious agent. In 2013, 1.5 million people died from TB and 9 million people became infected, with an estimated 2 billion latent global infections. TB is caused by the bacterium Mycobacterium tuberculosis (Mtb). Treatment of TB requires a lengthy, complicated drug regimen, which means that many patients fail to comply with the recommended course of treatment. Poor compliance, in turn, has led to the evolution of multi-drug resistant, extensively drug-resistant and totally drug-resistant TB (MDR-TB, XDR-TB and TDR-TB). MDR- and XDR-TB strains are difficult and costly to treat. In some instances XDR and TDR TB, few, if any, therapeutic agents remain. In conjunction with HIV infection, this deadly infection now presents us with a global time bomb that could devastate societies across the globe. The problem of TB is not confined to developing countries and in the last decade cases of TB have doubled in the UK with London now known as the TB capital of Western Europe. Mycobacterium bovis is a growing threat to livestock and can spread to humans causing TB There have been no new drugs to treat TB for > 40 years and there is thus a clear and pressing need for better, innovative, methods to treat and diagnose TB in the hope that we can find new weapons in the fight against this fearful pathogen. Mtb is unique from most bacteria that cause infection in that it has a distinctive, unusual cell wall. The cell wall has an unusually high fat and sugar content that provides a barrier to drugs, such as penicillin, and protects Mtb from the immune defence system. The majority of current antibiotic drugs are reliant on targeting a single biological process inside the bacteria; this approach, however, has lead to the resistance that is now widespread. As these targets are inside the bacteria, the drugs must be able to cross the cell wall to function, which in the case of TB, is hugely challenging. The aim of this innovative project is to challenge the current beliefs that exist in the field of anti-microbial research. Most drug searches focus on screening libraries of small molecules that fulfill a limited range of criteria (known as Lipinski's rule of 5) and focus on cell-well permeation potential. In this study the work will be carried out at the University of Warwick. The aim is to identify whether the unique cell wall of mycobacteria can itself prove to be a new target for therapies and/or diagnostics - essentially turning its own cell wall against itself. The objective of this work is to identify specific molecules that are able to bind to the unique cell wall sugars in the cell wall of mycobacteria and then to understand how this affects and disrupts essential cellular processes. This elegantly bypasses the need for drugs to reach an intracellular target - a major obstacle for anti-tubercular drug efficacy - and will exploit the unique nature of Mtb's cell wall to develop weapons against itself. The specific cell-wall binding process will also lead to potential diagnostic agents, increasing the value of this work. Potential applications and benefits resulting from this work are in the development of a new set of tools that can be used for diagnostics, and in identifying new drug targets for TB treatment. This work will stimulate untapped avenues and lead to paradigm shift in thinking to tackle the huge challenge of AMR. |
