Drug resistance in eukaryotic microorganisms

Abstract

Eukaryotic microbial pathogens are major contributors to illness and death globally. Although much of their impact can be controlled by drug therapy as with prokaryotic microorganisms, the emergence of drug resistance has threatened these treatment efforts. Here, we discuss the challenges posed by eukaryotic microbial pathogens and how these are similar to, or differ from, the challenges of prokaryotic antibiotic resistance. The therapies used for several major eukaryotic microorganisms are then detailed, and the mechanisms that they have evolved to overcome these therapies are described. The rapid emergence of resistance and the restricted pipeline of new drug therapies pose considerable risks to global health and are particularly acute in the developing world. Nonetheless, we detail how the integration of new technology, biological understanding, epidemiology and evolutionary analysis can help sustain existing therapies, anticipate the emergence of resistance or optimize the deployment of new therapies.

Figure 1. Timelines for emergence of drug resistance in parasitic diseases and fungi.

The solid bars represents the time from first widespread clinical use to the first year drug resistance was suspected or confirmed. The shading gradient indicates that certain drugs are still in use for particular indications or in specific geographical locations. NECT, nifurtimox–eflornithine combination therapy; VL visceral leishmaniasis. For fungal pathogens, insensitive or resistant strains have been identified shortly after the introduction of all of the major classes of antifungal agents. In the case of amphotericin B, there remains very little resistance — and differences in sensitivity mainly reflect the relative inherent sensitivity of different species to this agent.

Figure 2. Molecular mechanisms of drug resistance.

Eukaryotic microbial pathogens can exhibit drug resistance through reducing the overall intracellular concentration of the drug (less uptake, more efflux), by inactivating or failing to activate the drug, or by sequestering the drug away from its target. Resistance can also be mediated by reducing affinity of the drug for the target by mutation or by reducing the drug effect by overexpression of the target. Salvage and bypass pathways can also lower the overall impact of the drug action, as can the activation of pathways to repair any damage caused.