In acquiring resistance to one drug, many pathogens and cancer cells become hypersensitive to other pharmacons. This phenomenon, which is known as ‘collateral sensitivity’, could be exploited to combat existing drug resistance and to delay the emergence of resistance to new drugs. However, much remains to be understood about the mechanisms that underlie drug hypersensitivity in otherwise drug-resistant cells. This project seeks to provide detailed mechanistic explanations for collateral drug sensitivities induced by mutations in the Plasmodium falciparum ‘chloroquine resistance transporter’ (PfCRT). Mutant isoforms of PfCRT confer resistance to chloroquine (CQ) and to related quinolines by transporting these drugs away from their targets within the parasite’s digestive vacuole (DV) [1-4]. But these isoforms also increase the parasite’s sensitivity to a range of structurally-diverse drugs, including homodimers of quinine (Q2) . The additional killing effect of the Q2 drugs in CQ-resistant parasites has been attributed to their potent inhibition of the CQ-resistance-conferring isoforms of PfCRT (PfCRTCQR) . That is, through their ability to bind extremely tightly to the substrate-binding site of PfCRTCQR, the Q2 drugs are thought to block the normal physiological function of the protein (which is essential for the parasite’s survival [6, 7]) and thereby gain extra antiplasmodial activity against CQ-resistant parasites. We are undertaking a series of complementary in vitro and in situ assays (e.g., the Xenopus oocyte expression system and the H+ efflux assay) to test this hypothesis by measuring the ability of Q2 drugs to block the transport of PfCRT’s natural substrates (large peptides ) and thus establish whether PfCRT is itself a druggable target. Moreover, by examining the interactions of PfCRT with a new generation of Q2 drugs, as well as with homodimers of hydroxyl-CQ and primaquine, we are uncovering the properties that enable the Q2 drugs to exhibit heightened antiplasmodial activities against CQ-resistant parasites.