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One route to malaria drug resistance found
Date:7/24/2014

nce isoprenoids are necessary for life, it's not clear why the organism would purposefully slow down isoprenoid production.

"We don't know why the protein puts the brakes on under normal conditions," Odom said. "Perhaps simply because it's an energetically expensive pathway. But loss of PfHAD1 releases the brakes, increasing the pathway's activity, so that even when the drug is there, it doesn't kill the cells."

Odom says isoprenoid synthesis is an attractive drug target not just for malaria but for tuberculosis and other bacterial infections because these organisms also rely on this same isoprenoid pathway. While people make isoprenoids, these vital compounds are manufactured entirely differently in animals compared with many infectious pathogens likely to cause disease.

Inhibiting isoprenoid manufacturing in malaria, bacteria or tuberculosis, for example, would in theory leave the human pathways safely alone. In people, perhaps the most well-known isoprenoid is cholesterol, with statin drugs famously inhibiting that manufacturing pathway.

Odom, who treats patients at St. Louis Children's Hospital, said she sees a handful of malaria cases each year, mostly in patients who have recently traveled to parts of the world where malaria is common. The parasite remains a massive global health problem, causing about 627,000 deaths in 2012 alone, according to the World Health Organization. Most deaths are in children under age 5.

Despite this public health burden, malaria is understudied in the lab because it is notoriously difficult to grow. It has a complex lifecycle that includes two-way transfers between mosquito and human and spans different forms in the human liver and red blood cells.

"The malaria parasite is difficult to work with in the lab; it's nearly impossible to replicate the lifecycle," Odom said. "That's why it was so exciting to be able to do this kind of study in malaria, rather than in a typical mode
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Contact: Julia Evangelou Strait
straitj@wustl.edu
314-286-0141
Washington University School of Medicine
Source:Eurekalert  

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