Exploration of new therapeutic approaches and genetic and non-genetic adaptations in Plasmodium falciparum

<p dir="ltr">Infections with malaria are a major health burden that impacts global society and economy alike. The most dominant and lethal malaria-causing parasite is Plasmodium falciparum, which exhibits a high multiplication rate, efficient host cell invasion, potent cytoadherence, unique abilities to avoid the host's immune response, and countering treatment measures. The increasing occurrence of artemisinin-based combination therapy (ACT) treatment failure in P. falciparum stresses the discovery of new compounds that can either replace artemisinin as the first-line treatment, counter existing drug resistance, or function as a novel combination partners. Therefore, extensive evaluation of drugs and their targets is required to elucidate the full potential of treatment opportunities.</p><p dir="ltr">To increase our understanding of the parasite's opportunities to develop drug resistance, we evaluated the formation of resistance in P. falciparum, based on the heat shock protein 90 (Hsp90) inhibitor geldanamycin. Cyclic selection with incremental concentrations revealed a highly mutable geldanamycin target site, causing rapid adaptation to drug pressure. Interestingly, increased drug resistance was associated with the revertible upregulation of clag transcription, possibly allowing the parasite to elevate its resistance phenotype at a minimal fitness cost.</p><p dir="ltr">We further investigated the potential of nitric oxide (NO) donors for malaria treatment and evaluated the antiparasitic potential of the novel drug candidate PDNO in vitro. Our results demonstrated antiparasitic features of NO donors and uncovered enhanced properties for PDNO. These findings were elevated by an irreversible cytostatic effect upon repeated treatment, emphasizing its potential as an adjunct treatment option. However, we also revealed an antagonistic effect towards dihydroartemisinin and offer a mechanistic explanation, which suggests an incompatibility of NO donors for use in ACTs.</p><p dir="ltr">Collectively, these studies improve our understanding of drug resistance development in P. falciparum and emphasize the fitness-dependent interplay of genetic mutations and non-genetic alterations. Moreover, we describe the potential of a drug candidate and offer insight into the antagonistic mechanism of NO donors in combination with artemisinin.</p>