Starving the enemy

Malaria kills more than one million people each year, mostly young children. A further 500 million are infected annually, experiencing debilitating fevers and chills. Victims tend to live in tropical or equatorial countries, regions that provide the ideal habitat for the mosquitos that transfer the disease from person to person. In many of these places there is little money to go around. There is therefore little commercial incentive for pharmaceutical companies to develop new antimalarial drugs.

Much of the research into malaria and how to beat it is taking place in research institutions and university departments, including the School of Biochemistry and Molecular Biology (or BaMBi, as it is affectionately known to staff) at ANU. The fact that there is still no vaccine, for a disease that affects so many, and the fact that the parasite that causes the disease is becoming increasingly resistant to most of the available antimalarial drugs, suggests this is very serious work indeed. So why are scientists excited about shampoo?

Professor Kiaran Kirk and his colleague Dr Kevin Saliba, a lecturer in the Medical School, have worked together on the malaria problem for nearly nine years. They head up two distinct research teams in BaMBi, but collaborate and share an abiding interest in the fundamental biology of the malaria parasite.

“The focus of both of our groups is really the basic biology, biochemistry and physiology of the parasite,” Kirk says. “What are the mechanisms, at a cellular and molecular level, that the parasite relies on to stay alive?”

Once they have entered the blood stream from the bite of an infected mosquito the parasites first invade the liver and then, later, the red blood cells of their host, gradually destroying these cells while clogging the capillaries that carry blood to the brain and other organs. By living inside the host’s cells, the parasites evade detection by the immune system, while drawing on resources to survive from the surrounding plasma. Kirk believes that understanding the mechanisms by which substances are taken up into the infected cell and into the parasite within will pave the way for the development of new antimalarial strategies, as well as providing much-needed insights into how the parasite becomes resistant to antimalarial drugs.

“We’re working to understand how nutrients and drugs get into the cells, and how toxic waste products are released,” he says.

“These processes involve proteins that float around in the cell membranes, and which have the job of carrying nutrients, ions and metabolic wastes from one side of the membrane to the other.

“Looking at medicine in general, these types of proteins – so called membrane transport proteins – have a good track-record as drug targets. Many cardiac drugs, anti-ulcer drugs, anti-depressants and anti-hypertensives target human membrane transport proteins. In the malaria parasite-infected blood cell these sorts of proteins control traffic into and out of the infected cell, and the parasite inside, and we are exploring the potential of these proteins as antimalarial drug targets. We’re first trying to identify them, then understand what they do, then discover ways of stopping them.”

One line of enquiry that may eventuate in a new anti-malarial drug involves starving the bug by tricking it into taking up a false food.
“The parasite needs to take up the vitamin B5 from our plasma to survive,” Saliba explains. “If we can understand how the parasite takes this up and what it does with it, then that is a very good way to interfere with the parasite and be able to kill it.

“We’ve been working on it on and off for eight years. In the early days, we were looking at how the vitamin crosses the red blood cell membrane, and then how it crosses the parasite membrane. More recently we’ve been looking at what happens to the vitamin once it reaches the inside of the parasite.

“In the last couple of years we’ve also been working to find molecules that look like the vitamin, but which we might be able to use to trick the parasite into thinking it is taking up the vitamin but which, once inside, interfere with the biochemical pathways in which the vitamin is involved, thereby killing the parasite”

One of these trick compounds is called Pantothenol, which Saliba says is a common ingredient in many shampoos. He says that mammals are able to convert this compound into the vitamin B5, but malaria parasites cannot. Instead, pantothenol actually kills the parasite. Saliba and his team, including PhD student Christina Spry, are now trying to determine exactly where in the metabolic process the deathblow is dealt, collaborating with Dr Christina Chai from the ANU Department of Chemistry (now at ICES in Singapore) to develop similar compounds that will kill the parasite by the same mechanism. Saliba cautions that despite some promising results, the compounds need to be refined before a commercial application is considered.

“Developing a drug is still pretty far away. The analogues we have so far do kill the parasite, but the concentrations are still pretty high, meaning they could adversely affect mammalian cells. What we need is a compound that can kill the parasite at very low concentrations.”

While work on vitamin B5 analogues, and other classes of potential antimalarial agents continues, Kirk and Saliba are also collaborating on a study into the mechanism by which the parasite has become resistant to chloroquine, which was previously the most effective antimalarial available.

“The resistance mechanism involves membrane transport proteins which somehow cause the parasite to accumulate less drug,” Kirk says. “But understanding how they do this, and how we might stop them, is still a major challenge.

“The malaria parasite is a very cunning creature.  It hides inside the host cell, modifies the host cell in such a way to make it possible for it to live and replicate, and has mechanisms for becoming resistant to almost all of the drugs that have been developed.”

“It’s a very important problem, and it’s an increasing problem that affects a very large number of people. We hope that our work will lead to the identification of new antimalarial drug targets and the development of new control strategies.  Whether the next generation of antimalarials comes from our labs, or someone else’s, we hope our work here contributes to our understanding of the parasite and how it might best be combated.

“We both love the malaria parasite and spend much of our time thinking about it, but at the end of the day what we are trying to do is kill it. It’s a funny sort of relationship.”

Back to top