Scientists at Karolinska Institutet have
presented a new principle for fighting bacterial infections, in
other words, a new type of antibiotic, in the FASEB Journal. The new
antibiotic mechanism is based on selectively blocking the
thioredoxin system in the cells, which is crucial to the growth of
certain bacteria. Scientists hope to be able to treat such
conditions as stomach ulcers, TB and MRSA.
"Much work remains to be done, but we
believe that it will be possible to use this mechanism when, for
example, broad-spectrum antibiotics have proved to be inadequate",
says Professor Arne Holmgren, leader of the study now being
published.
The thioredoxin system is present in all
cells and is central to the ability to make new DNA (genetic
material). It is also important in protecting the cell from a
process known as oxidative stress, which arises when excess oxygen
radicals and other oxidizing agents are formed. This may occur, for
example, during the attack by white blood cells on bacteria, and it
can damage or kill the cell.
The most important components of the thioredoxin system are the
enzymes thioredoxin and thioredoxin reductase, of which the first
(very simplified) is required in the process of creating the
building bricks of what is to be new DNA, and the second ensures
that the thioredoxin remains active.
In addition to the thioredoxin system,
mammals and humans, and some bacteria, have a second, similar
biochemical process in the cell that is based on the enzyme
glutaredoxin. The thioredoxin system and the glutaredoxin system act
as each other's backup.
Many bacteria that cause disease, however, such as Helicobacter
pylori (which cause stomach ulcers), the TB bacterium Mycobacterium
tuberculosis, and the multiresistant staphylococcus bacterium MRSA,
have only the thioredoxin system. These bacteria lack the
glutaredoxin system. This makes these bacteria very vulnerable to
substances that inhibit thioredoxin and thioredoxin reductase.
"Furthermore, the thioredoxin reductases
in bacteria are very different in chemical composition and structure
from the human enzyme. And it is just these differences, and the
fact that certain bacteria lack the glutaredoxin system, that mean
that drugs that affect thioredoxin reductase can be used as
antibiotics. This is what we have discovered", says Arne Holmgren.
The study now being published describes
how the scientists have used a drug candidate known as ebselen,
which has previously been tested in the treatment of stroke and
inflammation. The scientists discovered that ebselen and similar
synthetic substances inhibit, among other things, thioredoxin
reductase in bacteria. The scientists saw in laboratory experiments
how the ebselen killed certain types of bacteria and not others.
They were able to modify the genetic properties of Escherichia coli
(E. coli), which is normally not susceptible to ebselen, and in this
way investigate the mechanisms behind the antibiotic effect. They
showed that the bacteria in which the genes in the DNA molecule that
code for the glutaredoxin enzyme or the formation of the tripeptide
glutathione, which is another important component of the
glutaredoxin system, had been switched off were must more
susceptible to ebselen than normal.
"It is particularly interesting that
MRSA and the antibiotic-resistant TB are also susceptible to ebselen
and new synthetic substances. And it's worth noting that ebselen is
an antioxidant, just as vitamin C is. This means that it protects
the host against oxidative stress, and in this way we can kill two
birds with one stone", says Arne Holmgren.
In addition to Arne Holmgren's research
group at Karolinska Institutet, scientists at Uppsala University,
the Swedish Institute for Communicable Disease Control, and the
World Health Organisation (WHO) have taken part in the study. The
work has been financed with grants from the Swedish Cancer Society,
the Swedish Research Council, Vinnova, the Knut and Alice Wallenberg
Foundation and Karolinska Institutet.
Publication:
Jun Lu, Alexios Vlamis-Gardikas, Karuppasamy Kandasamy, Rong Zhao,
Tomas N Gustafsson, Lars Engstrand, Sven Hoffner, Lars Engman, Arne
Holmgren
Inhibition of bacterial thioredoxin reductase: an antibiotic
mechanism targeting bacteria lacking glutathione
FASEB Journal, online 17 December 2012, doi:10.1096/fj.12-223305 ,
Vol. 27 April 2013
http://www.fasebj.org/content/early/2012/12/17/fj.12-223305.abstract
Karolinska Institutet
(MDN) |