Defective DNA Repair as a Potential Mechanism for the Rapid Development of Drug Resistance in Plasmodium falciparum

Abstract

The development and spread of highly drug-resistant parasites pose a central problem in the control of malaria. Understanding mechanisms that regulate genomic stability, such as DNA repair, in drug-resistant parasites and during drug treatment may help determine whether this rapid onset of resistance is due to an increase in the rate at which resistance-causing mutations are generated. This is the first report to demonstrate DNA repair activities from the malaria-causing parasite Plasmodium falciparum that are specific for ultraviolet light-induced DNA damage. The efficiency of DNA repair differs dramatically among P. falciparum strains with varying drug sensitivities. Most notable is the markedly reduced level of repair in the highly drug-resistant W2 isolate, which has been shown to develop resistance to novel drugs at an increased rate when compared to drug-sensitive strains. Additionally, the antimalarial drug chloroquine and other quinoline-like compounds interfered with the DNA synthesis step of the repair process, most likely a result of direct binding to repair substrates. We propose that altered DNA repair, either through defective repair mechanisms or drug-mediated inhibition, may contribute to the accelerated development of drug resistance in the parasite.

Plasmodium falciparum XPD translocates in 5′ to 3′ direction, is expressed throughout the blood stages, and interacts with p44

“…From Plasmodium's perspective, having altered or defective DNA repair pathways including NER could prove beneficial for the parasite to acquire mutations that may lead to development of drug-resistant phenotypes under drug pressure (Trotta et al 2004). From the point of view of successful anti-malarial drug development, it will be of immense importance to explore as to what extent and how DNA repair plays a role in development of drug resistance phenotype in P. falciparum (Trotta et al 2004).…”

“…From the point of view of successful anti-malarial drug development, it will be of immense importance to explore as to what extent and how DNA repair plays a role in development of drug resistance phenotype in P. falciparum (Trotta et al 2004). Although it is beyond the scope of this present study, yet, it motivated us to analyze few critical proteins involved in NER pathway in P. falciparum.…”

“…In P. falciparum, drugresistant phenotype has been associated with mutations in genes involved in drug transport, drug metabolism, and DNA repair (Miotto et al 2013;Petersen et al 2011). As suggested by few studies on mismatch repair (MMR) and UV-induced DNA repair in P. falciparum, defective or altered DNA repair machinery could be one of the likely factors leading to the development of reported resistant phenotypes (Castellini et al 2011;Trotta et al 2004).…”

pH Alkalinization by Chloroquine Suppresses Pathogenic Burkholderia Type 6 Secretion System 1 and Multinucleated Giant Cells

“…Moreover, the two studies employed different drugs with distinct modes of action. Whereas wortmannin specifically targets the type III phosphatidylinositol 3-kinase, CLQ's function is more comprehensive because it has also been reported to inhibit DNA repair, regulate cell-cell adhesion, etc., in addition to regulating other pH-dependent processes (42,43).…”

Expression and biochemical characterization of the Plasmodium falciparum DNA repair enzyme, flap endonuclease-1 (PfFEN-1)

“…This process generates free radicals and reactive oxygen species, which were shown to be a potent source of DNA damage in cells [1]. Given the high AT content of many Plasmodium genomes (approximately 70% and 90% in gene coding and non-coding regions, respectively) [2], other potential sources of DNA damage can include the spontaneous deamination of adenine (or guanine) as well as UV damage that can result in the formation of thymine dimers in the AT rich genome [3,4]. Repair of these damaged bases is likely to be essential for the survival of the parasites.…”