Monash University study shows how potent antimalarial drug kills the malaria parasite

Researchers from Monash University’s Institute of Pharmaceutical Sciences (MIPS) have discovered that ozonide antimalarials – a new class of antimalarial drugs - initially target the precarious ‘haemoglobin digestion pathway’ to kill malaria parasites.

During the blood stage of malaria infection, the parasite internalises and digests massive amounts of haemoglobin from the host red blood cell, leading to parasite growth and potentially patient death. In this study, the research team used a “multi-omic” approach to demonstrate that two of the leading ozonides disrupt the haemoglobin metabolism process, and in doing so kill the life-threatening parasite.

Ozonides are a class of fully synthetic antimalarial drugs with potent activity against all parasite species that cause malaria, including the deadliest: Plasmodium falciparum. 

Mosquito

With the emergence of resistance to current frontline antimalarials, new drugs are urgently needed and a clear understanding of their pharmacological effect is essential to optimise use in populations at high risk of contracting malaria.

In this current work, the team at MIPS, led by Associate Professor Darren Creek, studied the biological effects of two ozonides in Plasmodium falciparum parasites to gain new insight into their antimalarial mode of action.

Associate Professor Creek says: “By studying the biochemical effects of two of the leading ozonides, we found that not only do they disrupt haemoglobin digestion, they also impact parasite protein turnover.”

“Furthermore, when the duration of ozonide exposure was extended beyond three hours, additional parasite chemical processes were disrupted. These findings into the longer-acting effects of ozonides are exciting as it may provide enhanced antimalarial benefits compared to the existing short-acting artemisinin drugs.”

Malaria is a significant global health issue. In 2018 there was an estimated 228 million cases of malaria worldwide, with children aged under five years being the most vulnerable group affected by the disease.

Associate Professor Creek and his team used a multi-omics workflow to conduct their comprehensive analysis of the selected ozonides. This integrated approach collects a global view of changes in malaria parasite proteins, peptides and metabolites when treated with antimalarials.

“This study nicely demonstrates how the multi-omics platforms we’re harnessing at MIPS can be used to discover drug mechanisms. Improving our understanding of metabolic networks and mechanisms of drug action is an important step towards the discovery and development of new medicines for infectious diseases,” Associate Professor Creek said.

“Infectious diseases cause extensive morbidity and mortality, and emergence of drug resistance threatens to render many common bacterial and parasitic infections untreatable – our work focuses on the use of advanced technologies and methods to investigate drug action to improve health outcomes.”

Associate Professor Creek heads up the parasite metabolomics laboratory and the Monash Proteomics and Metabolomics Facility at MIPS. Current projects in the Creek lab focus on drug discovery for tropical diseases such as malaria, and the application of multi-omics technology in pharmaceutical and biomedical research.

The full study entitled System-wide biochemical analysis reveals ozonide antimalarials initially act by disrupting Plasmodium falciparum haemoglobin digestion can be read here