Scientists are making progress in their quest to find an improved
antibiotic for a strain of meningitis that results in over half a
million deaths a year worldwide. The fungal disease Cryptococcal
Meningitis is especially rife in AIDS patients and there are fears that
if new drugs cannot be found, it could become untreatable. The results
are published in one of the most respected journals in the field of
membrane biology - Biochimica et Biophysica Acta – Biomembranes. Further
experiments have been carried out at ISIS in the most recent ISIS run
cycle, which researchers hope will shed more light on the interaction
between the drug and the disease.
Cryptococcal Meningitis is diagnosed in nearly a million
people a year worldwide, mainly in AIDS patients but also in others with
defects in their cell mediated-immunity. More than 600,000 of these
cases lead to fatalities. Currently, there is no vaccine for
Cryptococcal Meningitis. Unlike most other strains of the disease, it is
not passed from person to person, but is actually acquired from the
environment, possibly by exposure to birds. The disease is most
prominent in Sub-Saharan Africa but is also known to be on the increase
in areas such as Thailand and India.
With funding from the
Engineering and Physical Sciences Research Council, scientists from
King’s College London have been using neutrons to look at the effects of
the antibiotic Amphotericin which is currently used to treat
Cryptococcal Meningitis. They hope this will help them devise new and
more effective treatments, in particular for the disease-causing fungi
that have developed a resistance to the drug.
“Such an approach,
of course, requires that we fully understand how Amphotericin works, and
unfortunately this is not the case”, said David Barlow – the lead
researcher from King’s College London.
“We do know that the drug
has little effect on the cells in a human because these cells are
surrounded by membranes containing cholesterol. We also know that the
drug exerts its effects on fungi because their cells do not contain
cholesterol, but instead have a related steroid, ergosterol. However it
is quite unclear how this difference between human and fungal cell
membranes matters to the workings of Amphotericin.”
Research published in the journal Biochimica et Biophysica Acta – Biomembranes
shows that Amphotericin can insert itself into cell membranes
regardless of whether they contain cholesterol, ergosterol, or no sterol
at all, and the resulting changes in the structure of the membrane seem
to be the same for all three systems. This means the reason for the
drug having less impact on human cells than fungal cells cannot purely
be down to the fact that human cells contain cholesterol – other factors
must be at play.
What seems more likely is that the drug
interacts more rapidly with fungal cells than human cells, or that the
structures it forms after inserting in to their membranes are different
for the two types of cell.
“We're now going on to investigate the
first of these possibilities, and during our next experiments at ISIS,
we plan to look for differences in the speed with which the drug enters
human and fungal cell membranes”, said David Barlow. “The more
information we can gather about how this complex system works, the more
likely we are to be able to develop a new antibiotic that will be as
effective as Amphotericin has been until recently”.
a world leader in epidemiology of fungal infections from the Centers
for Disease Control and Prevention in Atlanta, Georgia said: “New
treatment strategies are needed to reduce the mortality of this severe
infection– any developments in this field can only be a good thing”.
addition to Cryptococcal Meningitis, Amphotericin is also used to treat
infections such as the tropical disease Visceral Leishmaniasis.
Beth Penrose (ISIS)
Research date: April 2011