US scientists have analysed every gene in the most deadly malaria parasite for the first time to help identify and prioritise new drug targets, it was revealed last night (3 May 2018).
Researchers at the Wellcome Sanger Institute, Cambridge, UK, and University of South Florida (USF) believe they have unlocked the essential genes for Plasmodium falciparum, which is responsible for half of all malaria cases and causes 90% of fatalities, to determine which ones are indispensable.
To understand which genes the parasite needs, the researchers disrupted almost every one of its 5,400 genes and discovered that more than half were essential for the parasite to grow in red blood cells.
They made more than 38,000 mutations then looked for genes that had not been changed, which implied they were essential for the parasite to grow.
They found more than 2,600 of these essential genes, about 1,000 of which are conserved in all Plasmodium species and have unknown functions.
The findings are published in the latest edition of Science.
Senior author Professor John Adams, director of USF’s Center for Global Health and Infectious Disease Research, said: “What our team has done is develop a way to analyse every gene in this parasite’s genome. Using our genetic analysis tools, we’re able to determine the relative importance of each gene for parasite survival. This understanding will help guide future drug development efforts targeting those essential genes.”
Dr Julian Rayner, another senior author and senior group leader at the Wellcome Sanger Institute, added: “We need new drug targets against malaria now more than ever, since our current antimalarial drugs are failing.
“This is the first large scale genetic study in the major human malaria parasite, P. falciparum, and gives a list of 2,680 essential genes that researchers can prioritise as promising possible drug targets. We hope this functional genomics approach will help to speed up the pipeline to develop new treatments for this devastating disease.”
Plasmodium parasites have evolved resistance to many drugs and the spread of parasites resistant to artemisinin, the current front-line antimalarial drug, is an emerging threat.
How artemisinin kills parasites is still unknown, but it is thought that resistance could be linked to the proteasome pathway that degrades proteins in the cell. Many of the essential genes found in this study were in the proteasome pathway, which makes it a good target for overcoming artemisinin resistance.
Zhang M, Wang C et al. Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis.Science 3 May 2018; doi: 10.1126/science.aap7847
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