Potent Antimalarial Activity of Acriflavine In Vitro and In Vivo

Abstract

Malaria continues to be a major health problem globally. There is an urgent need to find new antimalarials. Acriflavine (ACF) is known as an antibacterial agent and more recently as an anticancer agent. Here, we report that ACF inhibits the growth of asexual stages of both chloroquine (CQ) sensitive and resistant strains of human malarial parasite, Plasmodium falciparum in vitro at nanomolar concentration. ACF clears the malaria infection in vivo from the bloodstreams of mice infected with Plasmodium berghei. Interestingly, ACF is accumulated only in the parasitized red blood cells (RBCs) and parasite specific transporters may have role in this specific drug accumulation. We further show that ACF impairs DNA replication foci formation in the parasites and affects the enzymatic activities of apicoplast specific Gyrase protein. We thus establish ACF as a potential antimalarial amidst the widespread incidences of drug resistant Plasmodium strains.

A CLAG3 Mutation in an Amphipathic Transmembrane Domain Alters Malaria Parasite Nutrient Channels and Confers Leupeptin Resistance

“…A positive result of either of these tests should alert the discovery program to the risk of this additional resistance mechanism. While older antimalarial drugs tended to be hydrophobic and not require channel-mediated uptake, newer antimalarial candidates often require PSAC-mediated uptake (45)(46)(47), possibly because of evolving guidelines on desirable chemical features of drug leads (48). Because the parasite may reduce uptake through either mutations or gene silencing, early screening of candidate antimalarials is warranted; compounds that access their intracellular target after uptake through this channel now have an additional liability and should be pursued with caution.…”

Small molecule inhibitors of Ago2 decrease Venezuelan equine encephalitis virus replication

“…More recently, it has been combined with other virostatics to treat HIV infection, using oral dosages up to 100 mg/day for seven days (Mathé et al, 1998). ACF is currently being studied for its potential to treat malaria in a mouse model (Dana et al, 2014) using intraperitoneal dosages of 5 mg/kg/day, and to reduce vascularization of tumor cells in a cell-based assay through its mediation of HIF-1 (Lee et al, 2009). Specifically relevant for treatment of VEEV, acridine compounds are known to cross the blood-brain barrier readily (Cornford et al, 1992) and there is evidence that ACF does so as well (Umschweif et al, 2013).…”

The ATP-dependent chromatin remodelling enzyme Uls1 prevents Topoisomerase II poisoning

“…However, a previous large-scale chemogenetic screen identified ACF as a drug that specifically kills uls1 Δ yeast (26) and we confirmed the potent toxicity of ACF (Fig 1A). ACF has been described as having antibacterial (27), antimalarial (28) and anti-cancer properties (29). This broad range of activity is likely due to the fact that ACF inhibits type II topoisomerase activity in vitro (28, 30).…”

“…ACF has been described as having antibacterial (27), antimalarial (28) and anti-cancer properties (29). This broad range of activity is likely due to the fact that ACF inhibits type II topoisomerase activity in vitro (28, 30). We show that in budding yeast, ACF acts as a Top2 poison rather than as a Top2 catalytic inhibitor.…”