Twilight brings out the worst in tropical Africa, Asia andLatin America. Namely, the anopheles mosquito,purveyor of malaria.

In the heyday of colonialism, white men in the tropicsgreeted nightfall with a "sundowner" _ a drink,invariably gin and tonic. The alcohol was the feel-goodingredient; the tonic, a source of quinine.

A South American tree _ discovered by Jesuit explorersin the 1500s _ secretes quinine in its bark. Exactly howthis alkaloid and its derivatives, stave off or mitigateinfection by malarial parasites remains a medical mysteryto this day.

Beginning in the 1930s, medicinal chemists have beendeveloping analogs of quinine far more effective than thecinchona original. The first, atabrine, gets credit forhelping to win World War II in the jungles of southeastAsia. Still more potent, even against malaria's deadliestparasite, Plasmodium falciparum, is the drug chloroquine.

So much so that it's causing its own downfall, amedicinal victim of drug resistance. "In fact, in SouthAmerica during the 1950s and 60s," recalls malarialparasitologist Dyann Wirth, "chloroquine was provided intable salt, as a prophylactic drug. And that," she added,"proved an excellent way to foster resistance, becausethere was always a low level of drug in the population, toselect for resistant parasites."

This extensive use of chloroquine is also edging it out ofanti-malarial efficacy in Africa and southeast Asia, Wirthpointed out, where P. falciparum rages increasinglyunchecked. So it's back to quinine, which so far resistsdrug resistance.

Two weeks ago at the Marine Biological Laboratory inWoods Hole, Mass., Wirth told the annual molecularparasitology meeting of her recent work in probing themechanism by which P. falciparum learns how to kiss offanti-malarial compounds, almost as fast as they can besynthesized.

Mating Yeasts Model Parasite Drug Expulsion

Wirth teaches tropical medicine at Harvard's School ofPublic Health. Her presentation to some 400 attendingparasitologists at Wood's Hole updated her paper in theSept. 12, 1995, Proceedings of the National Academy ofSciences (PNAS), titled: "Functional complementation ofthe ste6 gene of Saccharomyces cerevisiae with thepfmdr1 gene of Plasmodium falciparum."

"We hypothesize," Wirth told BioWorld Today, "thatantimalarial drug resistance works by means of a proteinor pump molecule in the parasite, which is able to pumpdrug out of the cell, thus preventing it from being killedby drugs."

She and her co-authors have developed an assay tomeasure this energy-dependent transport, or pumping,function in the cells of baker's yeast. "The assay," Wirthexplained, "measures the ability of the yeast cells to mate,which we think is mediated by the same kind of transport.Its mating factor, which is a small molecule somethinglike a drug, is actually exported from yeast cells in orderto signal yeast of the opposite mating type that matingshould occur."

She continued, "We were able actually to substitute themalarial parasite's gene and protein for this effluxfunction in yeast, and so directly measure transportmediated by this gene."

Her system will permit making site-specific mutants inthe gene and its resulting protein, "to see what effect thathas on the protein's ability to transport, in this case, themating factor. In parallel," she added, "we will be lookingat drugs that prevent this transport function as possibleleads for new antimalarials.

Besides the genetic effect within the organism, whichbrings on resistance due to heavy drug use, "there'sanother factor going on," Wirth pointed out. "That is apopulation effect: In the presence of chloroquine, themajority of the parasite population will be drug-resistant.But there may be a drug-sensitive minority, which issomehow able to be carried along.

"With removal of the drug," she concluded, "you mightsee a change in the population dynamics."

Inbred Parasites Too Indicted In Drug Resistance

Field study of those population dynamics in Papua NewGuinea has led malariologist Karen Day of OxfordUniversity to find that not drug over-use alone but in-breeding between strains of P. falciparum in endemicmalarial areas causes "rapid spread, and fixation, of drugresistance under selection pressure."

Day teaches at Oxford's Wellcome Center for theEpidemiology of Infectious Diseases. She reports herinbreeding study in the current issue of Science, datedSept. 22, 1995, under the title: "Mating Patterns inMalaria Parasite Populations of Papua New Guinea."

"The punch line of our study," Day told BioWorld Today,"that a high level of inbreeding marks the sex life of themalarial parasite in the mosquito, contrasts with findingsfrom colleagues who did a similar study in Tanzania,which showed much less inbreeding."

Day's laboratory consisted of six small Papuan villagesspread over 10 square kilometers. "Of their 400inhabitants," she said, "30 to 36 percent were infected,that is, carried the P. falciparum parasites. Children inparticular suffered from one to five febrile episodes ofmalaria a year." She contrasted this with sub-SaharanAfrica, "where malaria kills two million children a year."

Chloroquine is still "the front-line drug in treatingmalaria in Papua," Day observed, "but resistance to it isgrowing rapidly. Our aim is development of cheapantimalarial drugs that would last longer againstresistance, at the population level, not the individual."

So far, she added, "the emphasis of research has been onindividual patients rather than on the population ofendemic areas." Day is "waiting for Dyann Wirth and hercolleagues to come up with the resistance genes ofinterest. Then we will use mathematic measurements tocome up with molecular models, and take to the field." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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