tance is known to occur in vitro. At least one phenotype appears to be linked to resistance to mefloquine and halofantrine (Peters, 1990b).

Antimalarial Antibiotics Certain antibiotics, especially the tetracyclines and clindamycin, have useful antimalarial properties (Rieckmann, 1984; Kremsner, 1990). Erythromycin, chloramphenicol, and rifampicin have activity in vitro (Geary and Jensen, 1983) but have not yet found clinical application. Antimalarial activity is not found in the beta-lactam or aminoglycoside antibiotics.

The tetracyclines and clindamycin can cure falciparum malaria in humans. They show activity against P. vivax as well, and there is evidence that they act on liver- and blood-stage parasites. The resolution of symptoms and clearance of parasitemia occur slowly, however, and extended courses of therapy are needed to effect a cure. The most common use of the tetracyclines is in combination with quinine for the treatment of infections resistant to chloroquine or other drugs. In addition, prophylactic use of doxycycline has received recent attention (see above). While the tetracyclines and clindamycin can be used alone to cure uncomplicated cases of falciparum malaria, they have no advantages over other antimalarial agents when multidrug resistance is not a problem. Strains of P. falciparum with reduced sensitivity to tetracycline have been found. To avoid the selection of parasite strains resistant to them, the use of the tetracyclines and clindamycin should be restricted to cases in which resistance is a problem.

The antimalarial mechanism of action of the tetracyclines and clindamycin is unknown. It has been proposed that they inhibit protein synthesis in parasite mitochondria (Geary and Jensen, 1983; Prapunwattana et al., 1988), but this has not yet been proven. In this respect, the recent report that P. falciparum expresses a rifampicin-sensitive, prokaryotic-like RNA polymerase, apparently encoded in the mitochondrial genome, is extremely interesting (Gardner et al., 1991). Further research is needed to explain the surprising antimalarial properties of these antibiotics, which are generally not toxic to eukaryotic cells. Nothing is known about parasite mechanisms of resistance to antibiotics.

Drug Discovery and Development

Although botanical preparations—most notably cinchona bark—have been used to treat malaria for thousands of years, credit for the first efforts to systematically develop synthetic antimalarial agents belongs to the Germans (Schulemann, Schonhofer, and Wingler), who synthesized pamaquine in 1926 (see discussion of primaquine above). Outside of Germany, medicinal chemistry resources became the focus of the United States Cooperative Wartime Program during World War II. This program was coor-



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