5.5.3. Reparative Mechanisms

ROS generated by antimalarials damage many biomolecules, such as proteins, lipids, and nucleic acids [15]. Increased repair is therefore necessary for continued survival under elevated ROS production. The unfolded protein response (UPR), often referred to as a stress gene, is essential for parasite survival and is upregulated in K13 mutants. This confers upon the parasite an increased ability to repair or degrade proteins damaged by alkylation and oxidation generated by artemisinin [137]. Moreover, K13 mutations have been associated with the elevation of *P. falciparum* phosphatidylinositol-3-kinase (PfPI3K) due to its reduced association with PfKelch13 and polyubiquitination [138]. This consequently leads to the elevation of phosphatidylinositol-3-phosphate (PI3P), which is said to be essential in the trafficking of proteins and lipids toward the apicoplast, where they are needed [138,139]. K13 gene mutations have demonstrated a global spread and attracted increased attention, especially in endemic regions, as molecular markers for ART resistance [129], although not all have been linked to resistance to artemisinin [140,141]. Single-nucleotide polymorphisms (SNPs) in *P. falciparum mlh1*, *pms1*, and *exo1* lead to increased expression of thioredoxin (PfTrx) and signal peptide peptidase, which increases adaptation to oxidative stress and protein damage, leading to the upregulation of the DNA repair mechanisms of the parasite with a consequent decrease in the antimalarial effect of artemisinin [136,142]. These mechanisms keep the vital biomolecules of parasites functional and, as a result, improve their chances of survival under treatment, i.e., resistance development.
