Drug resistance in Leishmania: does it really matter?

Area of Science:

• Parasitology
• Infectious Diseases
• Drug Discovery

Background:

• Treatment failure (TF) is a major challenge in managing parasitic diseases like leishmaniasis.
• Drug resistance (DR) in parasites is often considered the primary cause of TF, but its direct link to treatment outcomes is debated.
• Current in vitro drug susceptibility assays may not accurately reflect in vivo parasite responses.

Purpose of the Study:

• To critically evaluate the methodologies used for measuring drug resistance (DR) in leishmaniasis.
• To assess the suitability of in vitro cultured parasites for studying drug resistance relevant to treatment failure (TF).
• To investigate alternative parasite-driven factors, such as quiescent forms, that may cause TF independently of measurable DR.

Main Methods:

• Review and critique of existing in vitro drug susceptibility assays for leishmaniasis.
• Analysis of parasite adaptation and genetic stability during in vitro culture.
• Exploration of the role of parasite dormancy and quiescent states in treatment recalcitrance.

Main Results:

• The study highlights significant ambiguities in the correlation between in vitro drug susceptibility and clinical treatment outcomes.
• Concerns are raised regarding the representativeness of in vitro adapted parasite strains for in vivo drug resistance studies.
• Evidence suggests that parasite factors beyond conventional drug resistance, like the development of quiescent forms, may contribute to treatment failure.

Conclusions:

• Current in vitro assays for measuring drug resistance in leishmaniasis may be insufficient to predict treatment failure.
• The use of in vitro cultured parasites requires careful consideration due to potential adaptation biases.
• Further research is needed to elucidate the role of parasite quiescence and other non-DR factors in leishmaniasis treatment failure.