Study of the apicoplast biology in Plasmodium falciparum during erythrocytic schizogony

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Dokumentart: PhDThesis
Date: 2018
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biochemie
Advisor: Duszenko, Michael (Prof. Dr.)
Day of Oral Examination: 2016-07-15
DDC Classifikation: 500 - Natural sciences and mathematics
Keywords: Plasmodium falciparum
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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.

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