Specific cytochrome P450 enzymes are essential for the biosynthesis of glycopeptide antibiotics such as vancomycin that are used as a last resort for the treatment of life-threatening bacterial infections. However, an increasing number of bacteria are developing resistances to these antibiotics as well. Researchers from the Max Planck Institute in Heidelberg are investigating the structure and function of these enzyme-antibiotics complexes in order to find ways to use P450s as biocatalysts for the semi-synthetic synthesis of glycopeptide antibiotic analogues that are effective against antibiotic-resistant bacteria.
Most bacterial infections have lost their capacity to cause terror thanks to antibiotics. However, the increase in antibiotic resistances is making the fight against bacterial pathogens rather difficult, and the widespread overuse and inappropriate use of antibiotics continues to fuel the increase in antibiotic-resistant bacteria. Strict surveillance strategies and hygiene rules have been in place for some years with the aim of ensuring the efficacy of new and existing antibiotics. However, bacteria are highly adaptable organisms and continue to remain a huge risk for human health.
There is an alarming rise in infections caused by bacteria that are resistant to common antibiotics. A particular problem is nosocomial (hospital-acquired) infections of newborns, for which a Germany-wide surveillance system has been established. Novel natural substances with an antibiotic effect might be able to contain the danger.
Many cancers are difficult to treat with drugs because they are resistant to them. A research group at Heidelberg is investigating the molecular mechanisms of multidrug resistance and has the goal to improve the treatment of cancer patients.
People who have survived a malaria infection often develop immunity to the disease. International malaria research is aimed at exploiting a person's natural immunity in order to treat malaria effectively and avoid resistance to previously effective drugs. These new approaches also raise hopes that one day countries at high risk of malaria may be able to eradicate the devastating disease.
Multidrug-resistant bacteria are resistant to many existing antibiotics and can be difficult to treat. There are increasing numbers of them worldwide. Although novel antibiotics are being developed, there are far too few of them to tackle the rise of multidrug-resistant bacteria. In Eastern Europe, doctors have been treating bacterial infections with viruses that infect bacteria, so-called bacteriophages, for almost 100 years.
In laboratory experiments Dr. Anja Apel from the University Hospital in Heidelberg proved that cancer cells that are resistant to radiation therapy can be made to become susceptible to this kind of treatment again by blocking the cells own recycling system.
Pancreatic tumours are among the cancers with the worst prognosis. In many cases they are resistant to treatment. Prof. Dr. Andreas Trumpp and his colleagues from the DKFZ and the Heidelberg Institute for Stem Cell Technology and Experimental Medicine HI-STEM have discovered that the reason why some pancreatic tumours are so resistant to treatment is down to larger quantities of the enzyme CYP3A5 in subtypes of pancreatic cancer. Molecular markers to differentiate the subtypes improve the diagnosis of the disease and enable the development of more successful individual therapies.
For bacteria, the environment is rather like a big market where they can give and receive new survival strategies if need be. A group of researchers led by Prof. Dr. Elisabeth Grohmann at the Freiburg University Medical Centre is investigating how microorganisms exchange antibiotic resistance genes. In a project involving two hospitals in Mexico City, the molecular biologists are also investigating whether pathogens, resistance genes and antibiotic residues enter the wastewater system and become part of the agricultural water cycle where they can potentially become a serious threat to human health.
More and more bacteria are developing resistance to multiple antimicrobial drugs. These multidrug-resistant bacteria can impede the action of common antibiotics via mutations or DNA transfer. More than 30,000 people are infected every year with multidrug-resistant bacteria in German hospitals alone. This could be prevented with appropriate hygiene measures and innovative test systems. Innovative test systems that enable reliable and rapid diagnoses have been developed in Baden-Württemberg, which is home to many research institutions and research-based medical companies.
CeCo Labs UG, founded as a spin-off from the University of Tübingen, has developed an internationally unique method for isolating bacterial cell walls. These are used in research to investigate antibiotic resistance, for example. Unlike conventional techniques, the method developed by CeCo Labs is able to supply a very high number of ultra-pure cell walls extremely quickly. Orders have already been placed by customers across the globe.
Pseudomonas aeruginosa has become an important cause of infection, and is often picked up in hospitals, especially by patients with weakened immune systems. It can cause respiratory and urinary tract infections, as well as lead to infections on implants and wounds. P. aeruginosa lives in a gel-like matrix, a so-called biofilm that is highly resistant to antibiotics, making it very difficult to eradicate. Dr. Alexander Titz and his team at the University of Konstanz are aiming to use the structure-based rational design of carbohydrate conjugates to render the pathogen harmless.
Some Enterococcus species are common commensal organisms in human intestines and other species are used in raw-milk cheese where they enhance flavour development. On the negative side enterococci are also a common cause of hospital-acquired infections. Prof. Dr. Johannes Huebner from the Freiburg University Medical Centre is hoping that the bacterias capsular polysaccharides might at some point in the future be used as a vaccine opening the door to new treatment options for often difficult-to-treat enterococcal infections.
Prof. Dr. Wilfried Weber who was appointed professor of synthetic biology at the Centre for Biological Signalling Studies bioss at the University of Freiburg in May 2009 has always had a great interest in the practical application of biology. Weber and his team have a thorough understanding of how different parts of signalling networks can be reassembled for specific purposes for example switching off the antibiotic resistance of bacteria.
Clostridium difficile is totally harmless in healthy people. However, in combination with antibiotics it can cause severe diarrhoea and intestinal inflammation in elderly and debilitated people. But how does the spore-forming, rod-shaped bacterium deploy its power? And how does it enter the cell? Dr. Panagiotis Papatheodorou and his colleagues from the Institute of Experimental and Clinical Pharmacology and Toxicology (Director: Prof. Dr. Klaus Aktories) at the University of Freiburg are trying to find answers to these questions. The researchers have identified the molecular mechanism that enables the C. difficile toxin to enter the cells of the intestinal mucosa. This finding possibly provides new approaches for treating C. difficile infections.
Bacteria adapt quickly to their environment and also to antibiotics. Many of the antibiotics used to treat bacterial infections have become ineffective as a great many bacteria have become resistant to them. Freiburg-based FreiBiotics GmbH is looking for completely new classes of antimicrobial substances. A screening method that has been developed over the last few years based on biosensors makes the identification of new substance classes more efficient at the same time as reducing the costs associated with their development.
Dr Michael Reth professor at the Max Planck Institute of Immunobiology and the University of Freiburg and some of his colleagues have recently uncovered the mechanism that foreign substances use to activate B cells of the immune system. The researchers were using synthetic biology methods long before this particular branch of science existed in its present form. Their results require a paradigm change and a revision of the reference books.
People’s life expectancy is increasing due to constantly improving medical treatment. One result of this is the greater wear of joints, which then need to be replaced with implants. Increased life expectancy means that the implants remain in the body for much longer and therefore need to be longer lasting. The revision rate of implant materials used in clinical practice is still as much as 10 per cent, particularly in the case of hip and knee joint implants (formation of wear particles, corrosion products). It is therefore necessary to develop new implant materials that help increase the life span of implants and reduce material failure.
Italian and German scientists have designed peptides to target the protein-protein interface of a key enzyme in DNA synthesis crucial for cancer growth. The peptides act by a novel inhibitory mechanism and curb cancer cell growth in drug resistant ovarian cancer cells. The multidisciplinary research project was led by the University of Modena and Reggio Emilia (UNIMORE) and the Heidelberg Institute for Theoretical Studies (HITS).
Antibiotics have long been used as all-purpose weapons against infectious diseases – too often and too early, as we now know. This tendency has caused many bacteria to become resistant to standard antibiotics. The search for new substance classes has proved quite difficult. Care must therefore be taken to use existing antibiotics prudently in order to reduce the number of bacteria becoming resistant to them in the long term. Researchers from IMTEK and BIOSS at the University of Freiburg have jointly developed a sensor platform to simultaneously quantify several antibiotics in human blood within a few minutes.
Heidelberg University Hospital and the University Medical Centre in Mannheim are working hard to counteract the increase of antibiotic resistance. Strategies include a European-wide system for infection surveillance, the training of health professionals in the responsible use of antibiotics and the search for novel antibiotic substances in unconventional organisms.
Bacteria will always find ways to defend themselves against substances such as antibiotics, thus inhibiting their effect. Many bacteria have pump systems that they use to actively remove antibiotic drugs from the cell. Prof. Kay Diederichs at the University of Constance is working on the elucidation of these mechanisms in order to produce useful information for the development of bacterial pump inhibitors.
Cells with irreparable DNA damage normally induce programmed cell death, or apoptosis. However, this mechanism often fails in tumor cells so that transformed cells are able to multiply and spread throughout the body. Scientists at the German Cancer Research Center have now discovered a possible cause of this failure.
Horizontal gene transfer between bacteria is a major reason for the spread of bacterial antibiotic resistance. It is the transfer of bacterial DNA from one bacterium to another, even distantly related species, by bacteriophages, viruses that infect bacteria. Microbiologists from the University of Tübingen are investigating these mechanisms with the aim of finding new strategies that would effectively combat bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), which is a troublesome bacterial strain in hospitals. In addition, the researchers are calling for more effective hygiene measures and are involved in the in-depth investigation of bacterial ecology.