The results of a recent study suggest that the resistance of microorganisms to antibiotics, in particular, is a major problem in everyday medicine because it has led to an exponential increase in the number of resistant microbes. A recent study, published in the journal Nature Communications, indicates that infections that already appeared to have been eradicated with modern drugs are once again a potentially fatal threat to humans. The situation is further complicated by the fact that more and more germs are appearing resistant not to one but to several antibiotics or other drugs.
Research is underway on the mechanisms used by microbes to defend themselves against substances that are toxic to them. One method is to actively transport toxic substances out of the cell before they can cause harm. Microbes use special membrane transport proteins for this purpose. In particular in eukaryotic microbes such as fungi which have a cell nucleus – unlike bacteria which do not have one – these membrane proteins are part of the family of ABC transporters (“ATP-binding cassette”). They export toxic substances by dividing the cellular energy transporter ATP.
As part of this study, a German-British research team led by Professor Dr Lutz Schmitt of the Institute of Biochemistry at HHU presented the three-dimensional structure of the yeast ABC transporter Pdr5 in several functional states. They determined these structures by single-particle electron cryo-microscopy, which makes it possible in particular to examine biological molecules in their natural form at very high resolutions by flash freezing them at low temperature. Not only did the research team show that Pdr5 is a central transporter protein in the creation of resistance conferred by the membrane protein, but they also used resolute structures to locate the drug-binding site and define the drug cycle. transport.
For more than 30 years, Pdr5 has been the model for PDR proteins in pathogenic fungi such as Candida albicans, responsible for candidiasis. The new findings help explain what, at the molecular level, allows a single membrane protein to prevent structurally diverse molecules from entering or efficiently transporting them out of the cell. The results can now be used as a basis for the design of new drugs in a targeted way to counter resistance.
For nearly 20 years, Professor Schmitt’s working group has been researching to explain how the transport protein works. The researchers managed to understand the structure by working with the group of Professor Dr Ben Luisi of the Department of Biochemistry at the University of Cambridge. At HHU, the research also involved Professor Holger Gohlke’s working group from the Institute of Pharmaceutical and Medicinal Chemistry and the Center for Structural Studies (led by Dr Sander Smits). (ANI)
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