Columbia University scientists capture images of how malaria resists drugs

Faced with malaria parasites that are rapidly developing resistance to traditional front-line drugs, scientists from the Columbia University Vagelos College of Physicians and Surgeons have started to unravel the question of how with a new imaging study.

The focus of their photos was PfCRT, a specific protein that mutates, allowing malaria to expel assaulting drugs–piperaquine (PPQ). It is the same protein also used to mediate resistance in the former first-line drug, chloroquine. In this study, scientists were able to track the protein with single-particle cryo-electron microscopy. PPQ has been the dominant force in malaria suppression for nearly 15 years, combining with artemisinin to cut related deaths from over 1 million in 2004 to an estimated 435,000 in 2017.

However, malaria resistance to PPQ is beginning to increase, particularly in Southeast Asia.

“The fight against malaria is stalling,” said David Fidock, the C.S. Hamish Young Professor of Microbiology & Immunology and study co-lead. “Uncovering the molecular underpinnings of resistance is essential to prolonging the effectiveness of current drugs and developing new ones.”

Fidock states that in some areas of Southeast Asia, PPQ and artemisinin are only 13 percent effective, which he says makes the drug “essentially useless” in those regions. He also believes that South America will be the next region hit.

The study also suggested ways drug potency could be restored.

“The PfCRT gene is difficult to sequence, so it’s been hard for people to monitor,” Fidock says, “There are hundreds of locations in PfCRT that could be mutated, but now we can say just look at these handful in the central cavity with specific structural and conservation properties. They are the only ones that can drive resistance.”

Combining antimalarials could be crucial, the scientists noted. They have also proposed the use of an agent to block PfCRT’s ability to transport anything — a sort of parasite-based screening system.