Achilles' heel of dangerous hospital pathogen
Structure of key enzyme unravelled - possible starting point for
antibacterial agents

Date:
April 6, 2022
Source:
Goethe University Frankfurt
Summary:
Researchers have shed light on the structure of an enzyme important
in the metabolism of the pathogenic bacterium Acinetobacter
baumannii. The enzyme 'MtlD' is critical for the bacterium's
synthesis of the sugar alcohol mannitol, with which it protects
itself against water loss and desiccation in dry or salty
environments such as blood or urine.

Structural analysis has revealed weak spots where it might be
possible to inhibit the enzyme and thus attack the pathogen.



FULL STORY ==========================================================================
Each year, over 670,000 people in Europe fall ill through pathogenic
bacteria that are resistant to antibiotics, and 33,000 die of the diseases
they cause.

In 2017, the WHO named antibiotic resistance as one of the greatest
threats to health worldwide. Especially feared are pathogens that are
resistant to several antibiotics. Among them, Acinetobacter baumannii
stands out, a bacterium with an extraordinarily pronounced ability to
develop multiresistance and, as a "hospital superbug," dangerous above
all for immunosuppressed patients.

Acinetobacter baumannii is highly resilient because it can remain
infectious for a long time even in a dry environment and thus endure on
the keyboards of medical devices or on ward telephones and lamps. This
property also helps the microbe to survive on dry human skin or in
body fluids such as blood and urine, which contain relatively high concentrations of salts and other solutes.


==========================================================================
The team from Research Unit 2251 of the German Research Foundation
led by Goethe University has now shed light on a central mechanism via
which Acinetobacter baumannii settles in such an adverse environment:
like many bacteria as well as plants or fungi, Acinetobacter baumannii
is able to synthesize the sugar alcohol mannitol, a substance excellent
at binding water.

In this way, Acinetobacter baumannii prevents desiccation.

Almost unique, however, is the way that Acinetobacter baumannii
synthesizes mannitol: instead of two enzyme complexes as are common in
most organisms, the two last steps in mannitol synthesis are catalysed
by just one. A team of researchers led by Professor Beate Averhoff and Professor Volker Mu"ller already discovered this "MtlD" enzyme with
two catalytic activities back in 2018. The team headed by Professor
Klaas Martinus Pos, who is also a member of the Research Unit, has now succeeded in shedding light on the enzyme's spatial structure.

He explains: "We've discovered that the enzyme is usually present in
the form of free monomers. Although these have the necessary catalytic activities, they are inactive. Only a dry or salty environment triggers
what is known as 'osmotic stress' in the bacterium, after which the
monomers aggregate as dimers. Only then does the enzyme become active and synthesize mannitol." The researchers have also identified which parts
in the structure are particularly important for the enzyme's catalytic functions and for dimer formation.

Professor Volker Mu"ller, spokesperson for Research Unit 2251, is
convinced: "Our work constitutes an important new approach for fighting
this hospital pathogen since we've identified a biochemically sensitive
point in the pathogen's metabolism. In the future, this could be the
starting point for customized substances to inhibit the enzyme."

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


========================================================================== Journal Reference:
1. Heng-Keat Tam, Patricia Ko"nig, Stephanie Himpich, Ngoc Dinh Ngu,
Rupert
Abele, Volker Mu"ller, Klaas M. Pos. Unidirectional mannitol
synthesis of Acinetobacter baumannii MtlD is facilitated by
the helix-loop-helix- mediated dimer formation. Proceedings
of the National Academy of Sciences, 2022; 119 (14) DOI:
10.1073/pnas.2107994119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220406101645.htm

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