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Overcoming antibiotic resistance
MUNICH, Germany—Targeted toward disarming a bacteria in multiresistant strains of Staphylococcus aureus (MRSA) bacteria and Mycobacterium tuberculosis, chemists at the Technical University of Munich (TUM) have discovered two hitherto unknown mechanisms of action that can be used to permanently disassemble a drug-resistant bacterial protease responsible for blocking the effects of antibiotics.
If this discovery leads to success, people suffering from MRSA staph infections and resistant tuberculosis may soon feel the effects of a super- treatment created by scientists to annihilate the bad bacteria and allow the medicine to work its magic.
Researchers around the world have been working diligently to find new ways of disarming the proteases in these resistant strains to combat them, TUM stated in a news release. At the heart of this effort lies the so-called ClpP protease, comprised of 14 subunits and a central regulatory function.
Proteases are among the most important types of protein, according to TUM. Like “molecular scissors,” they cut other proteins at given positions and thereby execute important cell functions. By cutting the amino acid chains to the right length or breaking proteins apart they can, for example, activate or deactivate proteins, decompose defective ones or switch signal sequences that serve to transport proteins to their proper position within a cell.
“However, the inhibitors used in the past have one decisive disadvantage,” states Stephan Sieber, who heads the Chair for Organic Chemistry II at TUM. “They don’t permanently disarm the proteins, but only stop them for a few hours. On top of that, to be effective they must attack all active centers of the protein.”
“We (have been) working on these issues since 2007, and have previously reported specific inhibitors of this protease,” Sieber tells DDNews. “The new discovery shows that these inhibitors act in different ways, highlighting the fact that the new mechanisms of protease may represent a more efficient way to inactivate this protease—and with longer lasting effects. It also contributes to a better mechanistic understanding of this protease.”
In collaboration with Prof. Michael Groll, who heads the Chair for Biochemistry at TUM, Malte Gersch and Roman Kolb, doctoral candidates at Sieber’s chair, have succeeded in uncovering two completely new mechanisms that can be used to permanently deactivate these important bacteriological proteases—in one case even without having to attack all active centers of the protein.
The first mechanism disrupts the arrangement of amino acids required for the cohesion of the protease subunits, Sieber says. As a result the protease breaks into two parts. The second acts directly on the core of the active center. It converts the amino acid that does the actual splitting into another kind of amino acid. The “scissors” thus lose their edge and the protein is rendered inoperable.
“Both approaches inhibit the protease in completely novel ways, and are thus very promising for the development of new forms of medication,” he says.
The scientists also found a whole series of inhibitors that initiate the two mechanisms, Sieber shares.
“Knowing the ways in which substances deactivate the proteases is a huge advance,” Gersch says. “We can now optimize the substances and possibly also apply the principle to other proteases.”
Sieber adds, “We aim to develop potent molecules against MRSA, but the current compounds are not there yet. They show activity against MRSA, but require careful pharmacological optimization before they can be tested. Right now it represents a proof of principle in vitro.”
Proteases are not only important for human cells, but for bacteria which also rely on them, Sieber notes. There are hardly any effective antibiotics left in the fight against pathogens like multiresistant strains of Staphylococcus aureus bacteria and Mycobacterium tuberculosis.
“MRSA is a disease of clinics occurring in developed countries,” Sieber explains. “Tuberculosis is a disease which is currently a big problem in less developed countries. The protease occurs in both pathogens, but has very different effects on the host.”
In medical facilities, MRSA, known in the U.S. as Methicillin-resistant Staphylococcus aureus, causes life- threatening bloodstream infections, pneumonia and surgical site infections, reports the Centers for Disease Control (CDC). In U.S. hospitals, MRSA causes more than 60 percent of staph infections.
Tuberculosis (TB) is a disease caused by bacteria that are spread from person to person through the air, the CDC states. TB usually affects the lungs, but it can also affect other parts of the body, such as the brain, the kidney or the spine. In most cases, TB is treatable and curable, but Multidrug-resistant TB (MDR TB) is caused by an organism that is resistant to isoniazid and rifampin, the two most potent TB drugs.
The German scientists also found a whole series of inhibitors that initiate the two mechanisms. Knowing the ways in which substances deactivate the proteases, Gersch says, “We could possibly also apply the principle to other proteases.”
In further research, Gersch and Sieber plan to test their substances on living bacterial strains to determine if these are truly inhibited in growth and pathogenic effect. Although the bacteria are not completely disarmed, they produce significantly fewer toxins that are conducive to inflammation.
The basic idea is to give the immune system more time to handle the pathogens on its own while the formation of new resistances is suppressed, they say.
The crystal structures were determined in collaboration with the synchrotron radiation source of the Paul Scherrer Institute in Villigen in Switzerland.
The TUM scientific group findings were recently published under the title, “Disruption of Oligomerization and Dehydroalanine Formation as Mechanisms for ClpP Protease Inhibition” in the Journal of the American Chemical Society.
“Our next step is to translate the discovery into pharmacological application,” Sieber says. “This would lead to inhibitors of bacterial virulence which could represent a new treatment option for multiresistant bacteria.”
Technische Universitaet Muenchen, or the Technical University of Munich, is one of Europe’s leading research universities, with 500 professors, 10,000 academic and non-academic staff, and 36,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai and São Paulo.