How resistant germs transport toxins at molecular level

Date:
September 20, 2021
Source:
Heinrich-Heine University Duesseldorf
Summary:
In order to counter the increasing threat posed by multi-drug
resistant germs, we need to understand how their resistance
mechanisms work.

Transport proteins have an important role to play in this process.

Scientists have now described the three-dimensional structure of
transport protein Pdr5, found also in a similar form in pathogenic
fungi.

The results could help develop mechanisms to combat dangerous
pathogens.



FULL STORY ========================================================================== Micro-organism resistance to antibiotics in particular is a major
problem in everyday medicine. This has seen the number of resistant
microbes increase exponentially. As a result, infections that appeared
to already have been eradicated using modern drugs now once again pose a potentially fatal threat to humans. The situation is further complicated
by the fact that more and more germs are emerging which are resistant
to not one but several antibiotics or other drugs.


========================================================================== Research is under way into the mechanisms used by microbes to defend
themselves against substances toxic to them. One method is to actively transport the toxic substances out of the cell before they can cause any damage. The microbes use special membrane transport proteins for this
purpose. In particular in eukaryotic microbes such as fungi that have
a cell nucleus -- unlike bacteria, which have none -- these membrane
proteins are part of the family of ABC transporters ("ATP-binding
cassette"). They export the toxic substances by splitting the cellular
ATP energy transporter.

In a current publication in Nature Communications, a German/UK
research team headed up by Prof. Dr. Lutz Schmitt from the Institute of Biochemistry at HHU has presented the three-dimensional structure of yeast
ABC transporter Pdr5 in several functional states. They determined these structures using single- particle cryo-electron microscopy, which makes
it possible to examine in particular biological molecules in their natural
form at very high resolutions by flash-freezing them to low temperatures.

Not only did the research team show that Pdr5 is a central transport
protein in creating the resistance conferred by the membrane protein,
it also used solved structures to localise the drug-binding site and
define the transport cycle.

For more than 30 years, Pdr5 has constituted the model for PDR proteins in pathogenic fungi such as Candida albicans, which causes Candidiasis. The
new findings help to explain what it is at molecular level that enables
a single membrane protein to prevent structurally diverse molecules from entering the cell or transport them out of the cell efficiently. The
findings can now be used as a basis for designing new drugs in a targeted
way to counteract resistance.

For almost 20 years, Professor Schmitt's working group has been
conducting research into explaining how the transport protein works. The researchers succeeded in understanding the structure by working together
with Prof. Dr. Ben Luisi's group in the Department of Biochemistry at
Cambridge University. At HHU, the research also involved the working
group of Prof. Dr. Holger Gohlke from the Institute of Pharmaceutical
and Medicinal Chemistry and the Center for Structural Studies (led by
Dr. Sander Smits).

========================================================================== Story Source: Materials provided by
Heinrich-Heine_University_Duesseldorf. Original written by Arne
Claussen. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Andrzej Harris, Manuel Wagner, Dijun Du, Stefanie Raschka, Lea-Marie
Nentwig, Holger Gohlke, Sander H. J. Smits, Ben F. Luisi, Lutz
Schmitt.

Structure and efflux mechanism of the yeast pleiotropic drug
resistance transporter Pdr5. Nature Communications, 2021; 12 (1)
DOI: 10.1038/ s41467-021-25574-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210920121747.htm

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