生物技术与生物材料

抽象的

A diversity of approaches to address the challenge of drug-resistance in malaria

Denis Zofou

For several decades, the phenomenon of drug resistance has remained the greatest challenge to malaria control, and it is part of the obstacles that sapped the dream of seeing malaria eradicated in the years 1970s. So far, resistance has been fully established in three of the five Plasmodium species responsible for human malaria (P. falciparum, P vivax and P. malariae). By WHO “drug resistance” is defined as “the ability of a parasite strain to survive or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the tolerance of the subject.” This definition originated in 1967 was later modified by adding that “the form of the drug active against the parasite must be able to gain access to the parasite or the infected erythrocyte for the duration of the time necessary for its normal action”. Cross resistance on the other hand is the simultaneous occurrence of resistance of the same parasite strain to two of more drugs belonging to the same drug family or exerting similar modes of action. Treatment failure is defined as “an inability to clear malarial parasitaemia or resolve clinical symptoms despite administration of an antimalarial medicine” [1]. Factors such as incorrect dosage, individual variations, host’s immune system, poor compliance in respect of the dose and duration of the treatment can equally lead to treatment failure, unlike drug-resistance which is an intrinsic property of the drug concerned. Malaria drug-resistance has led to enormous consequences including worsening of disease burden (increase mortality and morbidity), increased economic cost (cost of new drugs, increased socio-economical burden), and changes of disease management policies. Drug-resistance occurs as phenotype of mutation affecting parasite genome conferring evasion from drug targeting through any of the following mechanisms: drug inactivation or modification, active efflux, alterations in the primary site of action, alteration of metabolic pathway. Given the fact that the mutations are not deleterious to the survival or reproduction of the parasite, drug pressure will remove susceptible parasites while resistant parasites survive. Single malaria isolates have been found to be made up of heterogeneous populations of parasites lines with widely varying drug response characteristics, from highly resistant to completely sensitive [2,3]. Similarly, within a geographical area, malaria infections demonstrate a range of drug susceptibility.