Frankfurt scientists reveal atomic details for one of Legionella’s enzymatic weapons and develop first inhibitor
FRANKFURT. Antimicrobial resistance (AMR) is a major medical problem worldwide, impacting both human health and economic well-being. A new strategy for fighting bacteria has now been reported in the latest online issue of Nature by a research group headed by Prof. Ivan Dikic at the Goethe University Frankfurt. The scientists revealed the molecular action mechanism of a Legionella toxin and developed a first inhibitor.
As resistance continues to spread, common infections such as pneumonia and salmonellosis are becoming increasingly harder to treat. Two factors drive the AMR crisis: human negligence in the use of antibiotics and a lack of truly novel antibiotics for more than 30 years. According to a recent report by the World Bank, by 2050, AMR may reduce the global gross domestic product by 1.1% to 3.8%, depending on which scenario plays out.
Scientific efforts are underway to achieve better control of microbial infections. One promising approach is to limit damage to host cells and tissues in the course of a bacterial infection by blocking the microbial processes that cause such damage. The laboratory of Ivan Dikic, Director of the Institute of Biochemistry II at Goethe University, has been working in this field for the past decade. As Dikic explains: “We believe we can find new treatments that complement conventional antibiotics by targeting specific groups of bacterial effectors with rationally designed drugs. In this way pathogenic damage can be decreased, which helps patients better tolerate bacterial infection. This is a relatively new field that is attracting more and more attention in the community.”
To prove that this strategy is a viable option for tackling bacteria, Dikic’s team studies Legionella, which are known to cause pneumonia and are especially dangerous for immunocompromised patients. Recently, the Frankfurt scientists were involved in identifying a novel enzymatic mechanism that Legionella bacteria use to seize control over their host cells. Dr. Sagar Bhogaraju, who works at Goethe University’s Buchmann Institute for Molecular Life Sciences as part of the Dikic team, reports: “We showed that Legionella enzyme SdeA acts as a toxic bacterial effector. It promotes the spreading of bacteria by targeting the ubiquitin system, one of the cell’s powerful protection mechanisms against stress.”
Ivan Dikic’s group has now reported a further breakthrough in the journal Nature: they succeeded in solving the atomic structure of SdeA. “The enzyme is truly unique and catalyses a reaction in a two-step mechanism”, comments Dr. Sissy Kalayil, who is one of the lead Frankfurt scientists on the project. “Our results are very exciting as they reveal atomic details of this mechanism, and make the rational design of inhibitors possible.” In their publication, the researchers also reveal how this bacterial effector probably chooses its victim proteins within the host cell, exerting its effect by attaching ubiquitin to them. They also developed a first inhibitor blocking this reaction in vitro. “Our basic discovery has allowed us to prove that these enzymes are druggable,” Dikic comments. “But it is early days. There is a long road ahead of us before we will be able to use this novel mechanism therapeutically. And we will surely not stop here.” Most likely, Legionella is not the only bacterium using this mechanism.
Ivan Dikic’s group is located at the Institute of Biochemistry II (Medical Faculty) and the Buchmann Institute for Molecular Life Sciences at Goethe University Frankfurt. The group investigates the role of ubiquitin in human diseases including cancer, amyotrophic lateral sclerosis and infectious diseases.
Publication: Kalayil S*, Bhogaraju S*, Bonn F, Shin D, Liu Y, Gan N, Basquin J, Grumati P, Luo Z-Q, Dikic I. Insights into catalysis and function of phosphoribosyl-linked serine ubiquitination. Nature, Advanced Online Publication, DOI 10.1038/s41586-018-0145-8.
* Shared first authorship
In the same issue of Nature, there will be two articles published by the groups of Yue Feng (China) and Yuxin Mao (USA) which contribute additional details to the molecular mechanism of this unique enzyme (DOI 10.1038/s41586-018-0146-7 und 10.1038/s41586-018-0147-6
Link to images: www.uni-frankfurt.de/72116155
Caption: A detailed view of the 3D structure of the enzymatic active part of SdeA toxin (green). On the left, the essential catalytic surface is depicted in orange and the area for binding target proteins in purple. On the right, the amino acid residues involved in the reaction are highlighted. The detailed molecular picture now enables the design of suitable inhibitors. Source: Nature/Kalayil et al, Mai 2018
Information: Dr. Kerstin Koch, Institute of Biochemistry II, University Hospital Frankfurt, Phone: +49 69 6301 84250, email@example.com
Invasion has a long tradition and is being accelerated by globalisation, trade and tourism
FRANKFURT. Due to global trade and tourism, mosquitoes - transmitters of dangerous infectious diseases - have spread to almost every part of the world. Moreover, climate change promotes the spread of species that thrive under warmer temperatures even further. Scientists at the Goethe University and the Senckenberg Gesellschaft für Naturforschung have now compared the ecological niches of the Asian tiger mosquito and the yellow fever mosquito on various continents with the following result: “Due to its longer invasion time span of 300 to 400 years, the yellow fever mosquito has almost completely filled its niches in non-native areas, whereas the Asian tiger mosquito, with a shorter invasion time span of 30 to 40 years, has not yet arrived in all regions where they would find a suitable environment,” says Prof. Sven Klimpel.
“Over the next one to five decades, infectious diseases transmitted through vectors will increase” concludes Sven Klimpel’s team at the Goethe University and the Senckenberg Gesellschaft für Naturforschung. Vectors transmit agents that cause infectious diseases from a host to another organism without contracting the disease themselves. Many known vector species are native to tropical and subtropical regions. If vector species are established in a new area together with a disease agent, the area of risk for the associated disease will expand correspondingly.
Two prominent examples of vectors are the Asian tiger mosquito (Aedes albopictus) and the yellow fever mosquito (Aedes aegypti). The yellow fever mosquito is the main vector of the yellow fever virus, the dengue virus, the Zika virus and several other viral diseases. The tiger mosquito can also transmit the Zika virus and the dengue virus, but transmits other disease agents as well, such as the West Nile virus and the Chikungunya virus. These two medically relevant vectors are the focus of the current study in “Scientific Reports”.
The yellow fever mosquito, originally native to Africa, began to spread throughout the world 300 to 400 years ago – presumably with the expansion of sugar cane plantations and slave trade. The tiger mosquito, which today is considered one of the 100 worst invasive species, originally comes from South and Southeast Asia. Over the past several decades, it has been introduced and spread by trade and tourism, especially by the trade of automobile tires and lucky bamboo (Dracaena spp.). For example, tiger mosquito eggs, larva and pupae were transported great distances by sea, surviving in small water puddles inside used automobile tires, or in water containers for lucky bamboo.
In their study, the scientists investigated the ecological niches of both species in their native and non-native range, i.e., the totality of environmental conditions in which a species can occur. In their new ranges of distribution, mosquitoes can encounter different environmental conditions than in their native ranges. Invasive mosquito species are said to be especially quick to adapt to new climatic conditions. The scientists, however, found no evidence to support this. Both species occupy a broad niche and occur in a large number of different environmental conditions in their native ranges. Since similar climatic conditions prevail in the new distribution ranges, worldwide expansion cannot be explained by a niche expansion through adaptation, although local adaptation and genetic changes in species’ traits cannot be ruled out.
The scientists were, however, able to identify a difference between the two species: that time plays an important role in the expansion or invasion of a species. With its longer time span of invasion, the yellow fever mosquito almost completely fills its niche in the new, non-native distribution ranges; i.e. it occurs under many climatic conditions that also exist in its native distribution range.
The Asian tiger mosquito is a different case. In the new distribution ranges, it does not (yet) occur in all habitats that offer suitable climatic conditions. The researchers therefore predict a further expansion potential for this species in the future. Klimpel sums up: “The Asian tiger mosquito can already be found in nearly all southern European countries, and due to its broad niche, it will inevitably spread and establish itself in northern Europe as well. Further exotic mosquito species such as Aedes japoniucs (East Asian bush mosquito), Aedes koreicus or Aedes atropalpus will follow - or have already arrived - in Central Europe.“
Images may be downloaded at: www.uni-frankfurt.de/72048458
Copyright: photos from Dorian D. Dörge (Goethe University)
Sarah Cunze, Judith Kochmann, Lisa K. Koch, Sven Klimpel: Niche conservatism of Aedes albopictus and Aedes aegypti - two mosquito species with different invasion histories, in Scientific Reports, DOI:10.1038/s41598-018-26092-2
Information: Prof. Dr. Sven Klimpel, Institute for Ecology, Evolution and Diversity, Faculty of Biological Sciences, Riedberg Campus Frankfurt am Main, Tel. -49 69 798-42237, Klimpel@bio.uni-frankfurt.de
Stefan Knapp elected as member to the European scientific organisation for molecular biology, EMBO
FRANKFURT. Not everyone person who has a “cancer gene” will inevitably develop this disease in their lifetime. Thanks to a new area of research called epigenetics, we now know that many genes are only read under certain circumstances. Prof. Stefan Knapp from the Institute of Pharmaceutical Chemistry and Buchmann Institute of Molecular Life Sciences at the Goethe University not only researches the underlying mechanisms, he also developed small molecules that inhibit the derailment of gene expression in cancer. Now he has been elected as one of 62 new members in the European scientific organization for molecular biology, EMBO, joining a group of more than 1800 of the best researchers in Europe and around the world.
“I am delighted that I have been elected to the EMBO society and I am looking forward working with this group of outstanding scientists to advance research, exchange new ideas, and promote science in society”, says Stefan Knapp.
Prof Knapp has made seminal contributions to the elucidation of structural mechanisms of the regulation of proteins that play key roles in signal transduction. This in turn led to a detailed description of protein family specific regulatory mechanisms and the elucidation of substrate recognition processes. Based on these findings, he developed a large array of new small molecule inhibitors, in particular highly specific inhibitors for epigenetic reader domains.
The first potent inhibitor developed by Prof Knapp and colleagues validated epigenetic reader domains as target for cancer therapy which led to a diverse set of highly selective inhibitors targeting these proteins. Prof Knapp’s work has provided new insights into chromatin biology and paved the way for more than 25 clinical trials in this new area of drug discovery.
Prof Stefan Knapp studied Chemistry at the University of Marburg (Germany) and at the University of Illinois (USA). He did his PhD in protein crystallography at the Karolinska Institute in Stockholm (Sweden) (1996). In 1999, he joined the Pharmacia Corporation, where he worked for five years as a principal research scientist in structural biology and biophysics. In 2004, he set up a research group at the Structural Genomics Consortium at Oxford University (SGC). From 2008 to 2015 he was a Professor of Structural Biology at the Nuffield Department of Clinical Medicine (NDM) at Oxford University (UK) and between 2012 and 2015 he was the Director for Chemical Biology at the Target Discovery Institute (TDI). He joined Frankfurt University (Germany) in 2015 as a Professor of Pharmaceutical Chemistry and the Buchmann Institute of Molecular Life Sciences. He has been the CSO of the newly founded SGC node at the Goethe-University Frankfurt since 2017.
About EMBO // EMBO is an organization of more than 1800 leading researchers that promotes excellence in the life sciences. The major goals of the organization are to support talented researchers at all stages of their careers, stimulate the exchange of scientific information, and help build a European research environment where scientists can achieve their best work.
Further Information: Prof. Stefan Knapp, Institute of Pharmaceutical Chemistry and Buchmann Institute of Molecular Life Sciences, Faculty of Biochemistry, Chemistry and Pharmacy, Tel.: +49 (0) 69 798-29871, Knapp@pharmchem.uni-frankfurt.de
Climate researcher from the program “Make Our Planet Great Again“ coming from the US to the Goethe University
FRANKFURT. Following the Paris Climate Agreement, Germany and France created the program “Make Our Planet Great Again,“ to promote climate change research. One of 13 researchers selected by an expert jury of the German Academic Exchange Service (DAAD) is coming from the USA to the Goethe University in a few months.
The climate change researcher Dr. Anna Possner is leaving the renowned Carnegie Institution for Science in Stanford and will join the Department for Atmospheric and Environmental Sciences at the Goethe University. Thanks to a one million euro grant, she will start her own research group in Frankfurt. This group will cooperate with the Frankfurt Institute for Advanced Studies (FIAS), where it will also be located.
Anna Possner’s research focuses on layered clouds in the lowest kilometres of the atmosphere, which act as a semi-transparent parasol for Earth’s surface. They reflect a significant portion of incoming sunlight, but only marginally affect Earth’s heat emission. They thus have a cooling effect on Earth’s surface. Any sheet of low-level cloud may span hundreds of kilometres and all together they span around one fifth of Earth’s oceans. Changes in their areal extent or reflective properties can result in significant changes to Earth’s surface temperature.
In some regions of the globe, the mid-latitudes and the Arctic, these clouds consist not only of water drops, but may contain a mixture of ice particles and water drops. The proportion of water drops to ice crystals affects the clouds’ reflective properties. “While we have hypotheses about how the radiative properties may be affected within a single cloud,” Anna Possner explains, “we are limited in our understanding of how the presence of ice crystals impacts the areal coverage and reflective properties on the scale of an entire cloud field.” She will use satellite retrievals and sophisticated numerical models to help answer this question.
Since completing her doctoral dissertation at the ETH Zurich, Anna Possner, who was born in Jena, has studied the impact of particles on the reflective properties of clouds. During this time she focused in particular on low-lying clouds over the oceans, where she quantified and evaluated the impact of ship emissions on clouds. During her postdoc years at the ETH Zurich and the Carnegie Institution for Science in Stanford, she extended her analyses to include mixed-phase clouds.
The German-French program “Make Our Planet Great Again“ seeks to support the creation of solid facts as a basis for political decisions in the fields “climate change”, “earth system research” and “energy transformation”. Of the 13 scientists selected for Germany, seven are in the US, two were most recently working in Great Britain and one each is in Switzerland, Canada, South Korea and Australia. They were selected during a two-stage process out of approximately 300 applications.
Further Information: Prof. Joachim Curtius, Department for Atmospheric and Environmental Sciences, Faculty for Geosciences / Geography, Riedberg Campus, Tel.: +49 (0) 798-42058, firstname.lastname@example.org.
Empirical study on historical development allows a prognosis
FRANKFURT. Since first being awarded in 1901, most Nobel Prizes for science have gone to the USA, the United Kingdom, Germany and France. An empirical study by Professor Claudius Gros from the Institute for Theoretical Physics at the Goethe University in Frankfurt has now shown that the Nobel Prize productivity in these countries is primarily determined by two factors: a long-term success rate, and periods during which each country has been able to win an especially large number of Nobel Prizes.
For the study, Nobel Prizes for physics, chemistry and medicine were assigned proportionately, since up to three scientists can share the prize. The success rates were calculated on the basis of population figures. For France and Germany, the periods of increased scientific creativity occurred around 1900, whereas for the USA it occurred in the second half of the 20th century.
“The US era is approaching its end,” states Claudius Gros. “Since its zenith in the 1970s, US Nobel Prize productivity has already declined by a factor of 2.4.” According to his calculations, a further decline is foreseeable. “Our model predicts that starting in 2025 the productivity of the USA will be below that of Germany, and from 2028, below that of France as well.”
With a nearly constant, very high success rate per capita, Great Britain occupies a special position with regard to Nobel Prizes. It remains uncertain, however, whether Great Britain will be able to maintain this success, especially in view of the increasing industrialization of research.
“National research advancement can undoubtedly also be successful independent of Nobel Prize productivity,“ Claudius Gros stresses. “Especially because new areas of research such as the computer sciences – a typical US domain – are not included.” It therefore remains open whether the decline in Nobel Prize productivity is cause for concern, or merely an expression of a new orientation toward more promising research fields.
A chart to download can be found at: www.uni-frankfurt.de/71881831
Chart: Claudius Gros, Goethe University
Claudius Gros: An empirical study of the per capita yield of science Nobel Prizes: Is the US era coming to an end?, in: Royal Society Open Science (2018) http://rsos.royalsocietypublishing.org/content/5/5/180167
Claudius Gros: Pushing the complexity barrier: diminishing returns in the sciences, in: Complex Systems 21, 183 (2012). https://arxiv.org/abs/1209.2725
Further information: Prof. Claudius Gros, Department for Theoretical Physics, Faculty of Physics, Riedberg Campus, Tel.:+49(0)69 798-47818, email@example.com.