Abstract:
Parasitic diseases continue to be a leading cause of disability, morbidity, and mortality in tropical and subtropical regions of the world. Malaria, an acute and life-threatening disease, causing significant mortality, and schistosomiasis, a predominantly chronic disease leading to long-term morbidity, are often found together in the same geographical area, principally affecting people of low socioeconomic status. Artemisinin-based combination therapies are currently recommended by WHO for the treatment of patients with uncomplicated malaria. Recent reports from Southeast Asia show a delay in the clearance of malaria parasites from the bloodstream after treatment with artemisinin- based combination therapies. Thus, raising concerns that the parasites may spread from Southeast Asia to sub-Saharan Africa or occur de novo. Moreover, praziquantel is the only available drug for the treatment of schistosomiasis. However, this monotherapy presents with several challenges including that it is not active against juvenile worms and the cure rate is rarely 100%. A drug or drug combinations targeting the adult and prepatent life cycle stages of schistosomes would be more effective in treating patients and would significantly reduce pathogen transmission rates. The aim of this study was to assess the activity of compounds targeting organelles of prokaryotic descent, epigenetic regulators, and the hemozoin synthesis pathway in Plasmodium and Schistosoma parasites.
The first study evaluated antibiotics for their drug activity against P. falciparum and
S. mansoni. The novel synthetic halogenated tetracycline derivative eravacycline, together with tetracycline, tigecycline, doxycycline, and the lincosamide clindamycin, were evaluated for their drug activity against P. falciparum with the apicoplast investigated as a potential target. Moreover, clindamycin, doxycycline, mirincamycin, and tigecycline were tested against S. mansoni schistosomula in vitro. Eravacycline showed the highest activity of all the tetracyclines in the 3-day and 6-day assays against P. falciparum clinical isolates in Gabon. Antibiotics tested against S. mansoni were shown to be inactive in our study, though mirincamycin exhibited minimal activity. These findings show the potential of novel antibiotics, especially eravacycline, as candidate antimalarial therapies and interventions in concomitant infections.
In the second study, the in vitro potency of novel HDAC-inhibitors was evaluated against P. falciparum clinical isolates collected in Lambaréné, Gabon and surrounding area. The potency of 12 peptoid-based HDAC-inhibitors of human HDAC6 against asexual stages of P. falciparum clinical isolates was investigated. All HDAC-inhibitors demonstrated 50% inhibitory concentrations at nanomolar ranges. Peptoid-based HDAC6-inhibitors should be lead structures further evaluated for the development of antimalarial chemotherapeutics and to further investigate epigenetic regulators, including HDACs, as targets in Schistosoma parasites.
In the final study, 16 antiplasmodial compounds were evaluated against S. mansoni, for alternative treatment strategies of Schistosoma infections. Pyronaridine, methylene blue, and 5 other antiplasmodial compounds were highly active in vitro against the larval stage schistosomula with IC50s below 10µM. Mice infected with S. mansoni at the prepatent stage were treated with pyronaridine which reduced the worm burden by 82% and cured 7 out of 12 animals, though the adult stages remained viable. Though, on the contrary, methylene blue inhibited adult worms by 60%, but did not cure the mice. As part of an observational pilot study in Gabon, children with S. haematobium infections were treated with pyronaridine-artesunate (Pyramax), resulting in a reduction of eggs excreted in urine from 10/10 ml to 0/10 ml, and 3 out of 4 children were cured. Pyronaridine and methylene blue should be further investigated as candidates in humans in clinical studies for schistosomiasis treatment, since both are already approved for human use.
This thesis provides innovative data on novel inhibitors targeting organelles of prokaryotic descent, epigenetic regulators, and the hemozoin synthesis pathway in Plasmodium and Schistosoma parasites. These findings will contribute to further innovation of novel inhibitors used to increase control and elimination efforts for both parasitic diseases in endemic areas. Prospective work will further evaluate novel compounds in clinical studies in humans and potentially provide more information on the targets of each of these drug classes.