QUINOLINE RESISTANCE MECHANISMS IN PLASMODIUM-FALCIPARUM - THE DEBATEGOES ON

Despite considerable therapeutic success with the antimalarial 4-amino quinolines such as chloroquine, there is serious doubt about the futur e of this drug class due mainly to the development and spread of paras ite resistance throughout endemic areas. In this article we review the possible biochemical and molecular basis of resistance. Based on our current understanding we have considered the possibility of developing strategies which may allow the aminoquinolines to once again be used effectively against P. falciparum. Our conclusions are that drug resis tance is the result of a reduced rate of drug uptake which in turn red uces the amount of drug available to bind the target. The basis for th is reduced accumulation could be an altered pH gradient making the foo d vacuole more alkaline or the parasite cytosol more acidic, an efflux pump removing drug directly from the membrane or any other process wh ich will reduce the rate of drug uptake. Central to the effectiveness of this resistance mechanism is the transient availability of a high a ffinity, low capacity drug binding site (possibly haem) within the par asite. Resistance reversers such as verapamil influence the apparent K -a for this drug binding phenomenon via an increased drug uptake rate. We demonstrate that by chemical modification of the aminoquinolines, producing predictable alterations in their physicochemical properties, that it is possible to minimise the verapamil sensitive component of resistance and reduce significantly cross-resistance patterns without loss in absolute activity. Based on these views we suggest that the am inoquinoline antimalarials still have a role to play in the cheap, saf e and effective chemotherapy of falciparum malaria.