Plasmodium falciparum topoisomerases: Emerging targets for anti-malarial therapy

Different metabolic pathways like DNA replication, transcription, and recombination generate topological constrains in the genome. These topological constraints are resolved by essential molecular machines known as topoisomerases. To bring changes in DNA topology, the topoisomerases create a single or double-stranded nick in the template DNA, hold the nicked ends to let the tangled DNA pass through, and finally re-ligate the breaks. The DNA nicking and re-ligation activities as well as ATPase activities (when present) in topoisomerases are subjected to inhibition by several anticancer and antibacterial drugs, thus establishing these enzymes as successful targets in anticancer and antibacterial therapies. The anti-topoisomerase drugs interfere with the functioning of these enzymes and result in the accumulation of DNA tangles or lethal genomic breaks, thereby promoting host cell (or organism) death. The potential of topoisomerases in the human malarial parasite, Plasmodium falciparum in antimalarial drug development has received little attention so far. Interestingly, the parasite genome encodes orthologs of topoisomerases found in eukaryotes, prokaryotes, and archaea, thus, providing an enormous opportunity for investigating these enzymes for antimalarial therapeutics. This review focuses on the features of Plasmodium falciparum topoisomerases (PfTopos) with respect to their closer counterparts in other organisms. We will discuss overall advances and basic challenges with topoisomerase research in Plasmodium falciparum and our attempts to understand the interaction of PfTopos with classical and new-generation topoisomerase inhibitors using in silico molecular docking approach. The recent episodes of parasite resistance against artemisinin, the only effective antimalarial drug at present, further highlight the significance of investigating new drug targets including topoisomerases in antimalarial therapeutics.