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In the january issue of Chemistry and Biology,
researchers at Brandeis University and the University of Georgia
reported they have identified lead compounds
that inhibit Cryptosporidium�s parasitic punch, paving the way for an
effective antibiotic treatment. In all, scientists identified ten new
compounds, four of which are better at fighting Cryptosporidium than
the antibiotic paromomycin, the current gold standard for evaluating
anticryptosporidial activity.
�These are promising new compounds and this research provides an
avenue of much needed therapy for this disease,� said Brandeis
biochemist Lizbeth Hedstrom, whose lab identified the compounds
together with parasitologist Boris Striepen of the University of
Georgia.
While there are many drugs to treat bacterial infections, it has been
very difficult to find drugs against pathogens like Cryptosporidium
because the proteins of these parasites are actually very similar to
those of their human host. Scientists have been further thwarted
because little was known about Cryptosporidium metabolism. This
situation recently changed dramatically when genome sequencing
provided a genetic blueprint of Cryptosporidium.
In work leading up to the current study, Hedstrom and Striepen used
this blueprint to show that Cryptosporidium has a very simple process
to produce the building blocks of DNA and RNA. Surprisingly, the
researchers also discovered that Cryptosporidium stole a critical gene
in this pathway from intestinal bacteria. This unusually large
evolutionary divergence between parasite and host proteins provides an
unexpected platform for novel drug design.
The stolen bacterial gene encodes a gatekeeper protein, known as IMPDH,
which is essential for parasite growth. Hedstrom and her colleagues
set out to find compounds that bind to the part of the parasite�s
IMPDH that is most different from human IMPDH. They tested 40,000
compounds using the facilities of the National Screening Laboratory
for the Regional Centers of Excellence in BioDefense and Emerging
Infectious Disease (NSRB/NERCE) at Harvard Medical School, and
identified ten compounds that inhibited the parasite protein, but not
the human counterpart. Four of these compounds are effective in
stopping Cryptosporidium infection in the laboratory.
�The quest to develop drugs to treat this debilitating disease has
been almost futile,� said Hedstrom. �We are still a long way from an
actual anticryptosporidial drug, but we are very encouraged by these
results.�
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