Abstract:
Based on its prokaryotic nature, the apicoplast in Plasmodium falciparum is a unique
target with great potential for generation of both chemotherapeutic and immunization
intervention strategies against malaria. It is therefore essential to understand its
biology. This study used a drug based approach to explore new aspects of apicoplast
biology.
In part 1 of this study the established antibiotic clindamycin was used to study
biogenesis and function of the apicoplast during erythrocytic schizogony. The data in
this study showed that during erythrocytic schizogony, clindamycin inhibits the egress
machinery of the parasite by inhibiting the biogenesis and function of the apicoplast.
Interestingly, in order to egress from erythrocyte, these parasites rely on an unusual
early supplementation with isopentenyl pyrophosphate or zaprinast. The data in this
study further showed that, the apicoplast in P. falciparum is required during egress by
playing a role in the secretion of proteins required for egress. In this way, this study
expands the current understanding of the biology of the apicoplast and the mode of
action of this antibiotic during erythrocytic schizogony.
In part 2 of this study, experimental antibiotics called acyldepsipeptides (ADEPS)
were tested to determine whether they can target the biogenesis or function of the
apicoplast in P. falciparum during erythrocytic schizogony and therefore whether they
can be used as antimalarial drugs. The data in this study shows that ADEPS are able
to inhibit growth of P. falciparum. On one hand, in parasites containing the apicoplast
they appear to inhibit its biogenesis and or function. On the other hand, ADEPS also
inhibit the growth of P. falciparum parasite lacking the apicoplast. Consequently, in P.
falciparum, ADEPS appear to have apicoplast dependent targets and apicoplast
independent targets. Never-the-less, ADEPS appear to be active against P.
falciparum and therefore they can be invoked as antimalarial drugs. This study
therefore contributes to the expansion of the arsenal to combat malaria.
