Anti-disease therapy for malaria: 'resistance proof'?

Abstract

Antimalarial drugs have in the past fallen prey to resistance and this problem is likely to continue in the future. One approach to developing drugs that might be less prone to resistance might be to target the disease rather than the parasite itself. The rationale for this idea, which has been somewhat developed in antibacterial chemotherapy, is that drugs that can alleviate disease pathogenesis while not compromising the survival, growth or transmission of the pathogen should not exert selective pressure that would encourage the emergence and spread of resistance. This review considers (concentrating on possible interventions at the parasite level) whether such 'anti-disease' therapy could be developed for severe Plasmodium falciparum malaria, and if so whether it might be less prone to resistance. Several anti-adhesive treatments, aiming to reduce the tissue sequestration of P. falciparum-parasitised erythrocytes that is associated with cerebral malaria and other complications, have been investigated as 'adjunctive' therapies. These therapies are however unlikely to be 'resistance proof' because sequestration appears to enhance parasite survival in the host. Severe malarial anaemia is another potentially fatal complication of malaria that results not only from lysis of host erythrocytes by intracellular parasites but to a greater extent from lysis of unparasitised erythrocytes and impaired erythropoiesis. The possibility of therapy interfering with the last of these processes, which may be more 'resistance proof', is discussed in detail.