Are antivitamins the new antibiotics?
Researchers develops drug approach against bacterial infections

Date:
August 24, 2020
Source:
University of Go"ttingen
Summary:
Antibiotics are among the most important discoveries of modern
medicine and have saved millions of lives since the discovery of
penicillin almost 100 years ago. However, bacteria can develop
resistance to antibiotics which then leaves doctors struggling to
find effective treatments.

Researchers have now described a promising new approach involving
'antivitamins' to develop new classes of antibiotics.



FULL STORY ========================================================================== Antibiotics are among the most important discoveries of modern medicine
and have saved millions of lives since the discovery of penicillin
almost 100 years ago. Many diseases caused by bacterial infections --
such as pneumonia, meningitis or septicaemia -- are successfully treated
with antibiotics.

However, bacteria can develop resistance to antibiotics which then leaves doctors struggling to find effective treatments. Particularly problematic
are pathogens which develop multi-drug resistance and are unaffected by
most antibiotics. This leads to severe disease progression in affected patients, often with a fatal outcome. Scientists all over the world are therefore engaged in the search for new antibiotics. Researchers at the University of Go"ttingen and the Max Planck Institute for Biophysical
Chemistry Go"ttingen have now described a promising new approach involving "antivitamins" to develop new classes of antibiotics. The results were published in the journal Nature Chemical Biology.


========================================================================== Antivitamins are substances that inhibit the biological function of a
genuine vitamin. Some antivitamins have a similar chemical structure
to those of the actual vitamin whose action they block or restrict. For
this study, Professor Kai Tittmann's team from the Go"ttingen Center for Molecular Biosciences at the University of Go"ttingen worked together
with Professor Bert de Groot's group from the Max Planck Institute for Biophysical Chemistry Go"ttingen and Professor Tadgh Begley from Texas A&M University (USA). Together they investigated the mechanism of action at
the atomic level of a naturally occurring antivitamin of vitamin B1. Some bacteria are able to produce a toxic form of this vital vitamin B1 to
kill competing bacteria. This particular antivitamin has only a single
atom in addition to the natural vitamin in a seemingly unimportant place
and the exciting research question was why the action of the vitamin
was still prevented or "poisoned." Tittmann's team used high-resolution protein crystallography to investigate how the antivitamin inhibits an important protein from the central metabolism of bacteria. The researchers found that the "dance of the protons," which can normally be observed
in functioning proteins, almost completely ceases to function and the
protein no longer works. "Just one extra atom in the antivitamin acts
like a grain of sand in a complex gear system by blocking its finely
tuned mechanics," explains Tittmann. It is interesting to note that
human proteins are able to cope relatively well with the antivitamin
and continue working. The chemist de Groot and his team used computer simulations to find out why this is so. "The human proteins either do
not bind to the antivitamin at all or in such a way that they are not 'poisoned'," says the Max Planck researcher. The difference between
the effects of the antivitamin on bacteria and on human proteins opens
up the possibility of using it as an antibiotic in the future and thus
creating new therapeutic alternatives.

The research project was funded by the German Research Foundation (DFG).


========================================================================== Story Source: Materials provided by University_of_Go"ttingen. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Fabian Rabe von Pappenheim, Matteo Aldeghi, Brateen Shome,
Tadhg Begley,
Bert L. de Groot, Kai Tittmann. Structural basis for antibiotic
action of the B1 antivitamin 2'-methoxy-thiamine. Nature Chemical
Biology, 2020; DOI: 10.1038/s41589-020-0628-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200824131805.htm

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