Comparative Analysis of the Omics Technologies Used to Study Antimonial, Amphotericin B, and Pentamidine Resistance in Leishmania

Hindawi Publishing Corporation Journal of Parasitology Research Volume 2014, Article ID 726328, 11 pages http://dx.doi.org/10.1155/2014/726328 Review Article Comparative Analysis of the Omics Technologies Used to Study Antimonial, Amphotericin B, and Pentamidine Resistance in Leishmania Gagandeep Kaur and Bhawana Rajput University Avenue, College of Medical, Veterinary and Life Sciences, University of Glasgow, Lanarkshire G12 8Q, UK Correspondence should be addressed to Gagandeep Kaur; gagandeep Received 20 December 2013; Revised 24 April 2014; Accepted 28 April 2014; Published 12 May 2014 Academic Editor: C. Genchi Copyright © 2014 G. Kaur and B. Rajput. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Leishmaniasis is a serious threat in developing countries due to its endemic nature and debilitating symptoms. Extensive research and investigations have been carried out to learn about the mechanism of drug resistance in Leishmania but results obtained in the laboratory are not in agreement with those obtained from the field. Also the lack of knowledge about the mode of action for a number of drugs makes the study of drug resistance more complex. A major concern in recent times has been regarding the role of parasitic virulence in drug resistance for Leishmania. Researchers have employed various techniques to unravel the facts about resistance and virulence in Leishmania. With advent of advanced and more specific means of detection, further hints about probable mechanisms of conferring resistance are expected. This review aims to provide a consolidated picture along with a comparative account of the work done so far to study the mechanism of antimony, amphotericin B, and pentamidine resistance using various techniques. 1. Leishmaniasis: Incidence, Cause, and Resistance Leishmaniasis forms the ninth largest disease burden in the world affecting more than 90 countries on every continent except Antarctica and Australia (see http://www.cdc. gov/parasites/leishmaniasis/epi.html). It is an endemic disease with an estimated 12 million patients currently and a global rise of up to 2 million patients annually (see http://www.who.int/leishmaniasis/en/). The principal cause of the disease is Leishmania parasite. On the basis of symptoms, leishmaniasis can be classified into two forms—cutaneous and visceral. L. donovani, L. infantum, and L. chagasi are the causative agents of visceral leishmaniasis (VL). This form of the disease is characterized by fever, weakness, night sweats, hepatomegaly, or splenomegaly and is mainly reported in regions of India, Bangladesh, Sudan, Ethiopia, and Brazil. Cutaneous leishmaniasis (CL), on the other hand, arises as a sore at the site of insect bite which can proceed to a severe form at times. CL can take two forms: diffuse CL or mucocutaneous leishmaniasis. In diffuse CL, skin lesions are widespread on the body that resemble leprosy. Mucocutaneous leishmaniasis begins with ulceration in the nares that proceeds further to nasal septum, pharynx, or larynx. It can eventually lead to remarkable disfigurement in the patient. It is normally reported in Africa, Latin America, and Middle East. The causative agents for CL have been classified as old and new world species as follows [1, 2]: old world CL: L. major, L. tropica, L. (L.) aethiopica, and L. infantum; new world CL: L. (L.) mexicana, L. (L.) amazonensis, L. braziliensis, L. (V.) panamensis, L. (V.) peruviana, L. (V.) guyanensis, L. (L.) pifanoi, L. (L.) venezuelensis, L. (L.) shawi, and L. (V.) lainsoni. Female sand fly acts as a carrier to transmit the diseasecausing parasite into the host. Basically, the parasite enters the body of the host in metacyclic promastigote form. Thereafter, it transforms and multiplies into amastigote form [2]. Over 2 Journal of Parasitology Research Table 1: Drugs used for the treatment of leishmaniasis. Serial number 1 2 3 Name of the drug Mode of action Mode of administration Adverse effects References Pentavalent antimonials Inhibition of glycolysis and 𝛽-oxidation of fatty acids of parasite Intralesional for CL Parenteral Abdominal pain, erythema, nausea, toxicity (hepatic, pancreas, renal, muscular, and skeletal cardiothrombocytopenia or leukopenia) [2, 60, 61] Amphotericin B Binding to parasite’s membrane sterols and changing its permeability selective to K+ and Mg2+ Liposomal formulations Deoxycholate formulations Fever, nausea, hypokalemia, anorexia, leukopenia, kidney failure, and heart problems [2, 59–61] Pentamidine Interferes with DNA synthesis and modifies the morphology of kinetoplast Parenteral Intramuscular administration Pain, nausea, vomiting, dizziness, myalgia, hypertension, headache, hypoglycemia, and transient hyperglycemia [1, 2, 60, 61] Oral for VL Nausea, vomiting, diarrhea, and raised creatinine [1, 2, 59, 60] Topical for CL Parenteral for VL Erythema, pain, oedema, and ototoxicity (damage to internal ear) [1, 2, 60] 4 Miltefosine 5 Paromomycin Associated with phospholipid biosynthesis and alkyl-lipid metabolism in Leishmania Inhibition of protein biosynthesis in sensitive organism the years, a number of drugs have been employed for the treatment of the disease amongst which antimony (Sb) containing compounds called antimonials are the most preferred drugs worldwide. A brief account about the mechanism of action and mode of administration of these drugs has been presented in Table 1. The efficiency of these drugs depends upon (a) immune status of the host, (b) parasite factors, (c) drug pharmacokinetics [1, 3]. But despite so many treatment options, “drug resistance,” especially antimonial resistance, is a serious problem associated with Leishmania research. The seriousness of the issue can be assessed from the fact that there are regions in the world that have been reported of being completely resistant towards therapeutics. One such region is that of Bihar (India) which has been reported to be unresponsive towards pentavalent antimonial treatment [3]. Moreover, resistant strains for almost all existing drugs can be obtained under laboratory conditions [4–8]. Interestingly, there are instances of varying virulence in Leishmania parasite on attainment of drug resistance [9–12]. This supports the view that there exists a relation between virulence and drug resistance in Leishmania. Some scientists are of an opinion that drug resistance comes with a fitness cost. However, not much work has been conducted to relate drug resistance with virulence in order to scientifically support this hypothesis [12]. The present paper aims to provide an overall picture of the techniques used so far to study the area of drug resistance in Leishmania taking three major drugs (antimonials, amphotericin B, and pentamidine) into account and to highlight the (...truncated)