Bacteria's increasing resistance to antibiotics is a very serious medical issue. An infection with pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) bacteria can be life-threatening for hospital patients because MRSA has become resistant to the most commonly used antibiotics. Although reserve antibiotics are available in cases where others have lost their ability to control or kill bacterial growth effectively, they do not always work, and the development of resistance can make them even less effective. In the German Centre for Infection Research (DZIF), to which 35 institutions throughout Germany are affiliated, scientists from the University of Tübingen and their colleagues have developed a new drug which kills MRSA cells rapidly without affecting a patient’s natural microflora or promoting the development of resistance. In the coming months, the scientists will be preparing the compound for clinical testing.
Research into healthcare-associated antibiotic-resistant bacteria is one of several translational thematic units (TTUs) at the German Centre for Infection Research, which was established in 2012 to pool the expertise of numerous research institutions throughout Germany. Prof. Dr. Andreas Peschel from the Interfaculty Institute of Microbiology and Infection Medicine (IMIT) at the University of Tübingen coordinates this particular TTU. The microbiologist from Tübingen and his team have been focusing on the development of new drugs for the therapy of infectious diseases for quite some time.
A few years ago, microbiologists and infection researchers were still looking for new antibiotics, but this idea has now been largely abandoned despite the existence of a number of robust techniques to identify suitable antibiotics. "Unfortunately we always find compounds that belong to the same substance classes," explains Peschel. "This is why pharmaceutical companies have also curtailed their efforts to find new antibiotics."
One of the reasons antibiotic-resistant bacteria have evolved is down to the widespread use of broad-spectrum antibiotics, which are rather unspecific and kill nearly all the bacteria in a given patient. "This inappropriate use has increased selection pressure, causing more and more bacteria to develop resistances against more and more antibiotics," says the microbiologist, adding, "it is important to identify which pathogen has caused an infection and chose a drug that will specifically eliminate it. So, researchers have changed their strategy and are now looking for compounds that are specific for certain pathogens."
Staphylococcus aureus, which lives on the skin or in the nose of almost all healthy people, has become a particular problem. S. aureus is usually harmless, but under certain circumstances, for example during a hospital stay, can become a problem because hospitalised patients are more likely to be infected by S. aureus because of surgical or other wounds. In such cases, S. aureus infections can even lead to life-threatening infections. The infection can also easily spread to other patients. Methicillin-resistant Staphylococcus aureus (MRSA) strains are particularly feared because they have now become resistant to most antibiotics.
"All good hospitals therefore screen patients on admission for the presence of MRSA," says Peschel. "This helps considerably reduce the risk of MRSA infections. However, there is still the problem of how to eliminate the bacterium." One option is an antibiotic called mupirocin, which is used to treat bacterial infections, and is also useful for treating MRSA. However, several S. aureus and other bacterial strains have already become resistant to this drug. On top of this, "rehabilitation" of nasal mucosa and checks to see whether a patient is no longer carrying the bacteria take around a week. This is far too long, and impossible for patients about to undergo surgery.
DZIF scientists from the University of Tübingen, Münster and Munich have therefore taken a different approach to the development of a new antimicrobial. Along with a company called Hyglos GmbH based in the city of Bernried, the scientists have developed a completely new anti-MRSA drug. The compound is derived from bacteriophages (phages that infect and kill bacterial cells) and works by dissolving bacterial cells. "The protein is highly selective for Staphylococcus and causes the bacterial cells to burst. This happens so quickly that bacteria cannot become resistant. The drug, which the researchers call MRSA killer protein, was synthesised and modified in the laboratory under the name HY-133. The drug is easy to apply in the form of ointments. Test results have shown that all Staphylococcus cells – whether microbial-resistant or not – were killed. The natural microflora of the nose was not affected. The substance has therefore the potential to be used for the rapid and efficient treatment of at-risk patients.
Over the next few months, the drug will be prepared for preclinical and clinical tests aimed at assessing its efficiency for MRSA treatment. The DZIF is providing funding of more than 1.5 million euros for this purpose. The plan is to manufacture the drug according to GMP standards and have it ready in October 2015 or so, when the first preclinical toxicological and pharmacological tests are scheduled to take place. "We expect to be able to carry out the first human trials in about two years' time," says Peschel. Placing the drug on the market without undergoing the planned preclinical and clinical tests is not justifiable even though it will save the lives of thousands of people. "If it were a new antibiotic, we could do this. However, the enzyme is a very big molecule and we do not yet know whether it can diffuse through tissue and reach the bacteria inside the body."
Tests with cell cultures and animal models have been very promising. The researchers from Tübingen and other pharmaceutical experts now need to carry out tests to clarify that the designer protein is neither toxic nor allergenic.
The researchers have already optimised the designer protein to a degree that it has the desired stability. They used several parts of different phages, resulting in a combination of best-possible activity, specificity and stability. The compound is currently being produced on the laboratory scale in recombinant E. coli bacteria by Hyglos, the company that will subsequently market it. The researchers are currently looking for a competent partner interested in large-scale production of the enzyme. "We are currently in talks with several companies, but we are required to issue a European-wide call, which will prolong the procedure," says Peschel. "However, we are very confident that everything will work out as planned in four to five years' time. At which point, patients will be routinely given the compound prior to hospital admission. I am confident although there are still many things we need to take care of."