Physiological consequences of drug resistance in Leishmania and their relevance for chemotherapy

In the early twentieth century, infectious diseases were a leading cause of death worldwide. Through the following years, morbidity and mortality caused by infectious diseases decreased considerably in the developed world, but not in the developing world, where infectious diseases remain an important reason for concern. For example, leishmaniosis has become into a serious Third World problem. This is mainly due to an increasing frequency of drug-resistance in Leishmania and an enhanced risk of co-infection with HIV. Drug-resistance is usually associated with an increased expression of specific P-glycoproteins involved in membrane transport. The present review summarizes information which shows that drug-resistance is also associated with changes in physiological events such as parasite infectivity, incorporation of metabolites, xenobiotics conjugation and traffic, intracellular metabolism, host-parasite interaction, parasite cell shape and promastigote-amastigote differentiation. Furthermore, these events may change in a coordinated manner. An understanding of these physiological events may be helpful for designing chemotherapeutic approaches to multiple cellular targets, identifying strategies to circumvent Leishmania drug-resistance and succesfully treating leishmaniosis.