Drug Resistance in Leishmaniasis

Abstract

SUMMARY Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: Exploitation of GSK-3 for treating leishmaniasis

“…Leishmaniasis is also an important 58 public health and veterinary concern in Mediterranean countries (Dujardin, 2006). Chemotherapy 59 for leishmaniasis is generally ineffective mainly due to the emerging drug-resistance and severe 60 toxic side effects (Croft et al, 2006). Antimonials are used as first-line treatment despite their 61 toxicity.…”

“…Antimonials are used as first-line treatment despite their 61 toxicity. In case of antimonial resistance, liposomal formulations of amphotericin B, not devoid of 62 adverse side effects, are used (Croft et al, 2006). Miltefosine, the first oral drug, has proved to be 63 highly effective against visceral leishmaniasis.…”

“…However, miltefosine-resistant parasites have been 64 obtained in vitro indicating that there is a risk of resistance emerging in the field. Consequently 65 there is an urgent need to discover new targeted drugs against leishmaniases (Croft et al, 2006). 66…”

Contribution of proteomics of Leishmania spp. to the understanding of differentiation, drug resistance mechanisms, vaccine and drug development

“…Drug resistant parasites are a major problem in the field since leishmaniasis management relies on drugs 42 . However, the mechanistic reasons for drug resistance are only partially understood.…”

Toxicity of betulin derivatives and in vitro effect on promastigotes and amastigotes of Leishmania infantum and L. donovani

“…A large number of drugs have been used, but the therapeutics of leishmaniasis is hampered by the toxicity of some of the compounds, difficulties in administration in remote areas, the intraspecific variability of Leishmania drug sensitivities and the development of resistances, particularly in the case of L. donovani in India. 6,7 Moreover, in many countries, the use of first-line drugs (antimonials and amphotericins) is precluded by their high price. 8 Despite impressive advances in the understanding of the biology and molecular biology of Leishmania spp, these have not yielded any substantial improvements on chemotherapy; generally speaking, the compounds either already in use or undergoing clinical trials are incidental findings rather than the result of a directed research effort.…”