2002 ASCB Annual Meeting Press Book - page 9

December 14-18, 2002, San Francisco, CA
Unmasking Sleeping
Sickness: ‘Old’ Antibiotics
May Offer New Ways to
Treat a Third World Plague
All parasites are tricksters but
Trypanosoma brucei
, a
single-cell parasite that cycles between an insect form that
lives in the tsetse fly and a bloodstream form that lives in the
human host, is a master of the game. To move from fly to hu-
man host, the
T. brucei
must slip into an effective disguise to
hide from the immune system. Now researchers at the Johns
Hopkins School of Medicine led by Kimberly S. Paul have
blown the cover of
T. brucei
, catching the human bloodstream
form dressed in a self-synthesized coat of fatty acid-linked
proteins. Further, Paul and her colleagues found that the mo-
lecular pathway in the parasite that generates the fatty acid
coat is highly vulnerable to a commonly used antibiotic. This
opens the possibility of a new cheap and effective treatment,
a development that could have significant impact on human
health, especially in Africa. The bloodstream form of
T. brucei
causes African sleeping sickness, a disease that afflicts nearly
500,000 people today. If left untreated, it is fatal.
Although it was known for years that the insect form of
T. brucei
could synthesize fatty acids, it was thought that the
bloodstream form could not. Paul and her Hopkins collabora-
tors, Y. Morita, J. Stephens, and P.T. Englund, discovered that
the bloodstream form does, indeed, synthesize fatty acids,
specializing primarily in the fatty acid myristate. Myristate is
a critical component of the outer protein coat that protects the
parasite from attack by the host’s immune system.
The researchers then looked for ways to disrupt the pro-
cess. Using data from the
T. brucei
genome project, they iden-
tified several genes that may encode the enzymes that cata-
lyze fatty acid synthesis (FAS). Interestingly, they found that
some of these genes were structurally similar to the FAS genes
of bacteria (prokaryotes) rather than to those of animals (eu-
karyotes), which was surprising because
T. brucei
is eukary-
otic. Experiments that switched off or suppressed expression
in some of these genes indicated that the FAS pathway was
essential for the parasite’s growth and survival.
Given this pathway’s apparently vital role and its struc-
tural difference from the human host’s FAS pathway, the
Hopkins researchers decided to test the effect of known in-
hibitors of bacterial FAS on
T. brucei
including Triclosan, an
antibiotic commonly found in toothpaste and soap. Triclosan
directly inhibited the FAS pathway in cell-free enzymatic as-
says and inhibited the growth of
T. brucei
living in laboratory
cell cultures. “These data suggest that Triclosan and other
antibiotics that target
bacterial FAS could
represent a ready-made
pool of new drugs to
combat this lethal dis-
ease,” says Paul.
The sleeping sickness
parasite moves from the
feeding tsetse fly (above
right) into the blood
stream of a human host
where it dons a fatty acid coat that Paul and colleagues believe could
be vulnerable to an inexpensive antibiotic now used in toothpaste.
Clinics in sub-Saharan Africa (above left and below) are desperate
for new weapons against sleeping sickness. Images Courtesy of
World Health Organization/ Special Program for Research and
Training in Tropical Diseases (TDR).
Contact: Kimberly S. Paul, Johns Hopkins School of Medi-
cine, Biological Chemistry, Physiology Room 515, 725 N.
Wolfe St., Baltimore, MD 21205, (410) 955-3458
Prokaryotic Fatty Acid Synthesis in the Eukaryote Trypano-
soma brucei: A Pathway with Potential for New Drug Therapy
K. S. Paul, J. Stephens, P. T. Englund; Biological Chemistry,
Johns Hopkins School of Medicine, Baltimore, MD 21205.
At the meeting: Program 2809, B463, Structure & Function
of Membrane Proteins II. Author presents: Wednesday, De-
cember 18, 12:00 —1:30 PM.
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