Two of the most urgent challenges for scientists are the battles against food shortages and infectious diseases like malaria.
Unfortunately, both the herbicides used to protect plants and the anti-infectives that shield us from disease rapidly lose their effectiveness as the target organisms develop resistance.
In order to benefit both fields at once, scientists tested lead compounds from agrochemical research against infectious germs as well. In this way, a team of German and Swiss researchers has found a new candidate that may work against malaria, as they report in the journal Angewandte Chemie.
“Recently, enzymes from the non-mevalonate terpene biosynthetic pathway have been identified as attractive target structures with novel modes of activity for the development of herbicides and drugs against infectious diseases,” explains François Diederich from the ETH Zurich (Switzerland).
“This biosynthetic pathway is found in many human pathogens and in plants, but does not occur in mammals.” Correspondingly, an inhibitor should only have a toxic effect on pathogens and plants, not humans. Diederich and his co-workers at the ETH, TU Munich, BASF-SE, the University of Hamburg, the Swiss Tropical Institute STPHI in Basel, and TU Dresden have now discovered new inhibitors and characterized the ways in which they work.
By using high-throughput screening methods, the researchers of BASF SE led by Matthias Witschel tested about 100,000 compounds for an inhibitory effect against plant IspD, an enzyme of the aforementioned non-mevalonate terpene biosynthetic pathway – and found several hits.
The most interesting compounds are pseudilins, highly halogenated alkaloids from marine bacteria, and have a significant inhibitory effect on IspD, as researchers at the TU Munich led by Michael Groll demonstrated in NMR-based tests and researchers at the University of Hamburg led by Markus Fischer showed in photometric tests. Says Groll: “Interestingly, the chemical scaffold of the pseudilins is completely different from that of a previously discovered IdpD inhibitor. This suggests that the mode of action should also be different.”
To research this mechanism, Andrea Kunfermann from Groll’s team synthesized cocrystals of the pseudilins and IspD enzymes and examined them by X-ray crystallography. This showed that the pseudilins bind to an allosteric pocket in the enzyme. Halogen atoms in the pseudilins build up halogen bridges to the enzyme, which are, in addition to metal ion coordination, responsible for the strong binding. Occupation of this pocket changes the shape of the enzyme so that a cosubstrate required for proper functioning of the enzyme can no longer dock at the binding site in the active center.
“The pseudilins demonstrated herbicidal activity in plant assays and were active against Plasmodium falciparum, the pathogen that causes Malaria tropica and is dependent on the non-mevalonate biosynthesis pathway for survival,” reports Diederich. The researchers hope to use this as a new starting point for malaria treatment.About the Author
Angewandte Chemie International Edition, Permalink to the article: http://dx.doi.org/10.1002/anie.201309557
New Model of T Cell Activation
27.05.2016 | Albert-Ludwigs-Universität Freiburg im Breisgau
Fungi – a promising source of chemical diversity
27.05.2016 | Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie - Hans-Knöll-Institut (HKI)
A biological and energy-efficient process, developed and patented by the University of Innsbruck, converts nitrogen compounds in wastewater treatment facilities into harmless atmospheric nitrogen gas. This innovative technology is now being refined and marketed jointly with the United States’ DC Water and Sewer Authority (DC Water). The largest DEMON®-system in a wastewater treatment plant is currently being built in Washington, DC.
The DEMON®-system was developed and patented by the University of Innsbruck 11 years ago. Today this successful technology has been implemented in about 70...
Permanent magnets are very important for technologies of the future like electromobility and renewable energy, and rare earth elements (REE) are necessary for their manufacture. The Fraunhofer Institute for Mechanics of Materials IWM in Freiburg, Germany, has now succeeded in identifying promising approaches and materials for new permanent magnets through use of an in-house simulation process based on high-throughput screening (HTS). The team was able to improve magnetic properties this way and at the same time replaced REE with elements that are less expensive and readily available. The results were published in the online technical journal “Scientific Reports”.
The starting point for IWM researchers Wolfgang Körner, Georg Krugel, and Christian Elsässer was a neodymium-iron-nitrogen compound based on a type of...
In the Beyond EUV project, the Fraunhofer Institutes for Laser Technology ILT in Aachen and for Applied Optics and Precision Engineering IOF in Jena are developing key technologies for the manufacture of a new generation of microchips using EUV radiation at a wavelength of 6.7 nm. The resulting structures are barely thicker than single atoms, and they make it possible to produce extremely integrated circuits for such items as wearables or mind-controlled prosthetic limbs.
In 1965 Gordon Moore formulated the law that came to be named after him, which states that the complexity of integrated circuits doubles every one to two...
Characterization of high-quality material reveals important details relevant to next generation nanoelectronic devices
Quantum mechanics is the field of physics governing the behavior of things on atomic scales, where things work very differently from our everyday world.
When current comes in discrete packages: Viennese scientists unravel the quantum properties of the carbon material graphene
In 2010 the Nobel Prize in physics was awarded for the discovery of the exceptional material graphene, which consists of a single layer of carbon atoms...
24.05.2016 | Event News
20.05.2016 | Event News
19.05.2016 | Event News
27.05.2016 | Awards Funding
27.05.2016 | Life Sciences
27.05.2016 | Life Sciences