Researchers from Würzburg and Stony Brook have found a new weak spot in the bacterium that causes tuberculosis: Blocking a specific enzyme involved in the cholesterol catabolism could disable the bacteria.
In 2012, there were around 8.6 million cases of tuberculosis worldwide resulting in 1.3 million associated deaths according to the World Health Organisation WHO. About five percent of infections were caused by multidrug-resistant pathogens, a trend that is on the rise.
Scientists are therefore seeking new effective ways to tackle the tuberculosis bacteria in the future. Professor Caroline Kisker and her team have devoted their research to this topic: At the University of Würzburg’s Rudolf-Virchow-Center for Experimental Biomedicine, they are studying the bacterial enzymes to pinpoint new vulnerable points.
Enzyme-steroid interaction opens up new prospects
The Würzburg researchers are looking into the pathogens' cholesterol metabolism among others. The enzyme FadA5 is of major interest in this context as it is needed by the bacillus to keep up chronic infection. Teaming up with researchers of Stony Brook University (US), Kisker and her team have now analysed the exact structure of the enzyme – and identified a potential new target for drugs.
"We inserted a steroid molecule into the enzyme's active centre and analysed the resulting structure," the Würzburg professor explains. This finding helps to design molecules that fit exactly into the active centre and block it with the aim to completely disable the enzyme FadA5, as the research group reports in the January issue of "Structure" journal.
Drug specifically targets the bacterium
A potential problem, however, is that the human organism uses enzymes which are similar to the FadA5 from the tuberculosis bacilli. Hence, it is conceivable that a new drug not only affects the bacteria, but harms the human body as well.
Therefore, Kisker's team analysed the human enzymes, too. The result was promising: "Comparing the structures showed that it should be possible to block the bacterial enzyme specifically," the professor further. Thus, an inhibiting drug should only harm the bacteria but not the human enzymes.
"The steroid is a solid basis for us to develop new inhibiting drugs," Kisker says. To pursue this goal, she has teamed up with other work groups, including that of Professor Christoph Sotriffer of the Würzburg Pharmaceutical Chemistry Department. Their aim is to find a drug that specifically inhibits the FadA5 enzyme of the tuberculosis pathogens.
Schaefer et al.: "FadA5 a thiolase from Mycobacterium tuberculosis – a unique steroid-binding pocket reveals the potential for drug development against tuberculosis", Structure, published online, 2014, December 4, DOI: http://dx.doi.org/10.1016/j.str.2014.10.010
Prof. Dr. Caroline Kisker, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Phone +49 931 31-80381, email@example.com
Robert Emmerich | Julius-Maximilians-Universität Würzburg
New tool improves beekeepers' overwintering odds and bottom line
19.09.2019 | US Department of Agriculture - Agricultural Research Service
Elusive compounds of greenhouse gas isolated by Warwick chemists
18.09.2019 | University of Warwick
To process information, photons must interact. However, these tiny packets of light want nothing to do with each other, each passing by without altering the...
Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Hamburg and the European Molecular Biology Laboratory (EMBL) outstation in the city have developed a new method to watch biomolecules at work. This method dramatically simplifies starting enzymatic reactions by mixing a cocktail of small amounts of liquids with protein crystals. Determination of the protein structures at different times after mixing can be assembled into a time-lapse sequence that shows the molecular foundations of biology.
The functions of biomolecules are determined by their motions and structural changes. Yet it is a formidable challenge to understand these dynamic motions.
At the International Symposium on Automotive Lighting 2019 (ISAL) in Darmstadt from September 23 to 25, 2019, the Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, a provider of research and development services in the field of organic electronics, will present OLED light strips of any length with additional functionalities for the first time at booth no. 37.
Almost everyone is familiar with light strips for interior design. LED strips are available by the metre in DIY stores around the corner and are just as often...
Later during this century, around 2060, a paradigm shift in global energy consumption is expected: we will spend more energy for cooling than for heating....
Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Potsdam (both in Germany) and the University of Toronto (Canada) have pieced together a detailed time-lapse movie revealing all the major steps during the catalytic cycle of an enzyme. Surprisingly, the communication between the protein units is accomplished via a water-network akin to a string telephone. This communication is aligned with a ‘breathing’ motion, that is the expansion and contraction of the protein.
This time-lapse sequence of structures reveals dynamic motions as a fundamental element in the molecular foundations of biology.
10.09.2019 | Event News
04.09.2019 | Event News
29.08.2019 | Event News
19.09.2019 | Physics and Astronomy
19.09.2019 | Health and Medicine
19.09.2019 | Life Sciences