Trypanosomatid parasites of the genus Leishmania are the causative agents of
leishmaniasis, a
neglected tropical disease with several clinical manifestations. Leishmania major is the causative agent of
cutaneous leishmaniasis (CL), which is largely characterized by ulcerative lesions appearing on the skin. Current treatments of
leishmaniasis include pentavalent antimonials and
amphotericin B, however, the toxic side effects of these drugs and difficulty with distribution makes these options less than ideal.
Miltefosine (
MIL) is the first oral treatment available for
leishmaniasis. Originally developed for
cancer chemotherapy, the mechanism of action of
MIL in Leishmania spp. is largely unknown. While treatment with
MIL has proven effective, higher tolerance to the
drug has been observed, and resistance is easily developed in an in vitro environment. Utilizing stepwise selection we generated
MIL-resistant cultures of L. major and characterized the fitness of
MIL-resistant L. major. Resistant parasites proliferate at a comparable rate to the wild-type (WT) and exhibit similar apoptotic responses. As expected,
MIL-resistant parasites demonstrate decreased susceptibility to
MIL, which reduces after the
drug is withdrawn from culture. Our data demonstrate metacyclogenesis is elevated in
MIL-resistant L. major, albeit these parasites display attenuated in vitro and in vivo virulence and standard survival rates in the natural sandfly vector, indicating that development of experimental resistance to
miltefosine does not lead to an increased competitive fitness in L. major.