Nav: Home

Researchers map druggable genomic targets in evolving malaria parasite

January 11, 2018

Researchers at University of California San Diego School of Medicine, with colleagues across the country and around the world, have used whole genome analyses and chemogenetics to identify new drug targets and resistance genes in 262 parasite cell lines of Plasmodium falciparum -- protozoan pathogens that cause malaria -- that are resistant to 37 diverse antimalarial compounds.

The study, published in the January 12 issue of Science, confirmed previously known genetic modifications that substantially contribute to the parasites' drug resistance, but also revealed new targets that deepen understanding of the parasites' underlying biology.

"This exploration of the P. falciparum resistome -- the collection of antibiotic resistance genes -- and its drug-able genome will help guide new drug discovery efforts and advance our understanding of how the malaria parasite evolves to fight back," said senior author Elizabeth Winzeler, PhD, professor of pharmacology and drug discovery in the Department of Pediatrics at UC San Diego School of Medicine.

P. falciparum is a unicellular protozoan transmitted to humans through the bite of infected Anopheles mosquitos. It is responsible for approximately half of all malaria cases. Malaria's massively disproportionate impact on human health -- the World Health Organization estimates there were 216 million cases worldwide and 445,000 deaths in 2016 -- is due in part to the parasites' particular adeptness at changing genomes to evade and resist drug treatment and the human immune system.

"A single human infection can result in a person containing upwards of a trillion asexual blood stage parasites," said Winzeler. "Even with a relatively slow random mutation rate, these numbers confer extraordinary adaptability. In just a few cycles of replication, the P. falciparum genome can acquire a random genetic change that may render at least one parasite resistant to the activity of a drug or human-encoded antibody."

Such rapid evolution poses significant challenges to controlling the disease, said researchers, but it can also be exploited in vitro to document precisely how the parasite evolves in the presence of known antimalarials to create drug resistance. It can also be used to reveal new drug targets.

Rather than focus upon the interaction of parasites to single compounds or investigate single suspect genes in P. falciparum, Winzeler and colleagues used whole genome sequencing and a diverse set of antimalarial compounds. The resulting dataset revealed a diversity of mutations. Resistant parasites often contained a mutation in a presumptive target gene and additional mutations in other, unrelated genes.

"Our findings showed and underscored the challenging complexity of evolved drug resistance in P. falciparum," said Winzeler, "but they also identified new drug targets or resistance genes for every compound for which resistant parasites were generated. It revealed the complicated chemogenetic landscape of P. falciparum, but also provided a potential guide for designing new small molecule inhibitors to fight this pathogen."
-end-
Co-authors are: Annie N. Cowell, Erika L. Flannery, Matthew Abraham, Gregory LaMonte, Roy M. Williams, Victoria C. Corey, Christin Reimer, Purva Gupta, Olivia Fuchs, Erika Sasaki, Sang W. Kim, Christine Teng, Lawrence T. Wang, Sabine Ottilie and Dionicio Siegel, UC San Diego; Eva S. Istvan and Daniel E. Goldberg, Washington University School of Medicine, St. Louis; Amanda K. Lukens and Dyann F. Wirth, Harvard T.H. Chan School of Public Health and The Broad Institute; Tomoyo Sakata-Kato, Pamela Magistrado and Selina Bopp, Harvard T.H. Chan School of Public Health, Boston; Maria G. Gomez-Lorenzo, Virginia Franco, Maria Linares, Ignacio Arriaga and Francisco-Javier Gamo, GlaxoSmithKline, Madrid, Spain; Manu Vanaerschot, Nina F. Gnädig, Olivia Coburn-Flynn, James M. Murithi, Pedro A. Moura and David A. Fidock, Columbia University College of Physicians and Surgeons; Edward Owen, Heather J. Painter and Manuel Llinás, The Pennsylvania State University; Paul Willis, Medicines for Malaria Venture, Geneva, Switzerland; Olga Tanaseichuk, Yang Zhong and Yingyao Zhou, Genomics Institute of the Novartis Research Foundation, San Diego; and Asli, Akidil, Sophie Adjalley and Marcus C.S. Lee, Wellcome Sanger Institute, UK.

University of California - San Diego

Related Malaria Articles:

Could there be a 'social vaccine' for malaria?
Malaria is a global killer and a world health concern.
Transgenic plants against malaria
Scientists have discovered a gene that allows to double the production of artemisinin in the Artemisia annua plant.
Fighting malaria through metabolism
EPFL scientists have fully modeled the metabolism of the deadliest malaria parasite.
Should we commit to eradicate malaria worldwide?
Should we commit to eradicate malaria worldwide, asks a debate article published by The BMJ today?
Investigational malaria vaccine shows considerable protection in adults in malaria season
An investigational malaria vaccine given intravenously was well-tolerated and protected a significant proportion of healthy adults against infection with Plasmodium falciparum malaria -- the deadliest form of the disease -- for the duration of the malaria season, according to new findings published in the Feb.
Why malaria mosquitoes like people with malaria
Malaria mosquitoes prefer to feed -- and feed more -- on blood from people infected with malaria.
Malaria superbugs threaten global malaria control
A lineage of multidrug resistant P. falciparum malaria superbugs has widely spread and is now established in parts of Thailand, Laos and Cambodia, causing high treatment failure rates for the main falciparum malaria medicines, artemisinin combination therapies (ACTs), according to a study published today in The Lancet Infectious Diseases.
Considering cattle could help eliminate malaria in India
The goal of eliminating malaria in countries like India could be more achievable if mosquito-control efforts take into account the relationship between mosquitoes and cattle, according to an international team of researchers.
Seasonal malaria chemoprevention in Senegalese children lowers overall malaria burden
Giving preventive antimalarial drugs to children up to age 10 during active malaria season reduced the cases of malaria in that age group and lowered the malaria incidence in adults, according to a randomized trial carried out in Senegal and published in PLOS Medicine by researchers from the Université Cheikh Anta Diop, Senegal, the London School of Hygiene & Tropical Medicine, UK, and other collaborators.
How malaria fools our immune system
OIST researchers reconstruct the 3-D structure of a malaria protein in combination with human antibodies.

Related Malaria Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Don't Fear Math
Why do many of us hate, even fear math? Why are we convinced we're bad at it? This hour, TED speakers explore the myths we tell ourselves and how changing our approach can unlock the beauty of math. Guests include budgeting specialist Phylecia Jones, mathematician and educator Dan Finkel, math teacher Eddie Woo, educator Masha Gershman, and radio personality and eternal math nerd Adam Spencer.
Now Playing: Science for the People

#518 With Genetic Knowledge Comes the Need for Counselling
This week we delve into genetic testing - for yourself and your future children. We speak with Jane Tiller, lawyer and genetic counsellor, about genetic tests that are available to the public, and what to do with the results of these tests. And we talk with Noam Shomron, associate professor at the Sackler School of Medicine at Tel Aviv University, about technological advancements his lab has made in the genetic testing of fetuses.