trans

ACKNOWLEDGMENT 293
humans; babesiosis, theileriosis, sarcocystosis,
and neosporosis in cattle; and coccidiosis
in poultry. Treatments for most of these diseases
are less than optimal (see Chapter 17).
What relevance does the plastid have for
diseases caused by these parasites? Much of
the current effort against malaria is based on
vaccines directed against bloodstream stages
of the parasite and typically directed at surface
antigens. Malaria’s photosynthetic ancestry
probably has little or no bearing on these antigens
or the ultimate success of the vaccines.
However, more efficacious drug treatments for
malaria and toxoplasmosis would be useful
adjuncts to a vaccine, and it is in this area that
the plastid could have enormous implications.
The apicoplast appears to contain ribosomes,
and the genome encodes both protein
and RNA components of ribosomes, making it
likely that the parasite plastid contains machinery
to express its information content. This
machinery, which represents a third genetic
compartment in these cells, is a potential
target for therapeutics. A number of antibiotics
inhibiting either transcription or translation
in prokaryotic-like systems can block
mitochondrial and/or plastid function.
Interestingly, some also inhibit growth of apicomplexan
parasites. For instance, bacterial
translation blockers like doxycycline, thiostrepton,
spiramycin, and clindamycin inhibit
malaria growth. No direct evidence for action on
apicoplast translation for these compounds
is yet available, but it seems likely that the
anti-malarial activity derives from plastid
inhibition. Further up the information chain,
rifampicin (a blocker of bacterial transcription)
is also anti-malarial and ciprofloxacin
(which blocks bacterial-type DNA replication)
stops apicoplast genome replication and kills
parasites. These pharmacological phenomena
strongly suggest that the apicoplast is an excellent
drug target.
The above-mentioned parasiticidal agents
are thought to act on the apicoplast’s genetic
machinery, blocking genome expression at various
levels. Further downstream there is also
potential for pathway inhibition. Antibacterials
with targets in the fatty acid biosynthetic
machinery such as thiolactomycin (FabF and
FabH), triclosan (FabI) and arylphenoxypropionate
herbicides (ACCase) have anti-malarial
or anti-toxoplasmodial activity. Isoprenoid
biosynthesis has also been targeted by fosmidomycin,
which blocks deoxyxylulose phosphate
synthase, an enzyme unique to plastids
and the bacteria from which they derive and
absent from eukaryotic organisms without plastids.
The apicoplast therefore presents itself
as a promising, parasite-specific target with
a wide selection of pathways that can be targeted
with drugs. Significantly, a large body
of detailed information about these pathways,
the enzymes involved and the modes of
action of a number of specific inhibitors is
already available from studies of bacteria and
plant chloroplasts. This information is a fantastic
springboard for exploration of novel
drug options for disease management. The
tremendous success of antibiotics directed
against bacteria stems from their specificity.
Because they target prokaryote-specific functions,
antibacterials generally have few contraindications.
Protozoan, fungal and viral
diseases, on the other hand, are more difficult
to treat as they share many of the host’s
metabolic processes. The Apicomplexan plastid,
therefore, presents a unique, and potentially
exploitable, difference between host and
parasite.
ACKNOWLEDGMENT
The author thanks David Roos for Figures 12.1B
and 12.2, and Guy Brugeroke for Figure 12.1C.
BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA