LONDON Tom Wellems in the United States says it's taken him 15 years. David Warhurst in the UK says he's been studying the problem since 1963. Many others have been worrying at the issue at least as long. But now Wellems at the US National Institute for Allergy and Infectious Diseases (NIAID) and colleagues have pinned down the first of the serious drug resistances, chloroquine-resistant
Wellems dubs the affected gene
David Warhurst, Professor of Protozoal Chemotherapy at the London School of Hygiene and Tropical Medicine, who has been privileged to work with Wellem's data for some months before publication, told BioMedcentral, "It seems clear that this is a very important result, and that these particular mutations may be the primary change that occurs in chloroquine resistance. The level of resistance they create is low, but they may open the gate to higher resistance by additional mutations. It doesn't say that explicitly in the paper, but having worked in this area for years, that's how it seems to me."
Chloroquine is still the cheapest and safest of the malaria drugs, but different degrees of resistance, from slight to total, have arisen throughout the tropics since its trumpeted introduction in the late 1940s. It still works in China, and in Central America and North Africa. In the 1950s, in combination with DDT against mosquitoes, it was expected to help eliminate malaria from the world — but resistance set in, first in South-East Asia in 1957, and then in South America in 1959. Moving from East to West, it covered tropical Africa between 1978 and 1985. Other drugs, such as mefloquine, halofantrine, pyramethamine and more recently artemisinin derivatives are far more expensive, and difficult for the poorest countries to afford. Yet malaria is said to kill 700,000 under-fives each year in Africa alone.
Wellems and co-workers made a false start three years ago, when his group reported another gene, dubbed
According to Wellems, "
But haven't other genes on other chromosomes been related to drug resistant malaria in the past, BioMedcentral asked Warhurst? "There's been data on chromosome 5 since 1990, which looked as though it could pinpoint chloroquine resistance to the
"There is more evidence this time than there was for
"But I don't suppose this is the end of the story" he said. "Mefloquine resistance and artemisinin resistance, for example, seems to be mainly
So what might
Malaria parasites feed on haemoglobin from the host, but that produces a waste product, hemin — iron in a porphyrin ring — which is toxic to the parasite. Normally the hemin polymerises into a form the parasite can eliminate. But chloroquine — and several other drugs including amodiaquine, quinine, mefloquine and halofantrine — complex with hemin and interrupt the polymerisation, leaving the toxic hemin and killing the parasite. Artemisinin, artemether and artesunate also interfere with the iron metabolism, releasing free radicals.
Careful optical work with fluorescent dyes by one of Wellems' team, Paul Robey, has shown that the
But "whatever the details, the discovery of
This may lead chemists towards creating long-lived new drugs, according to Wellems. "If we can mimic the action of chloroquine with another drug that beats the
However it is not clear how far this will really speed up drug development. It can take 15 years and up to $500 million to get from a research idea to a drug in the field. Wellems says that any modifications of chloroquine will have to be tested for side-effects, and so "this discovery may not reduce the cost of developing a substitute for chloroquine. Phase I, II & III trials, the packaging, dosing and distribution are going to cost as much as for any drug".