Review Article
Drug resistance in leishmaniasis: Newer developments Sarita Mohapatra Department of Microbiology, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
ABSTRACT
KEY WORDS
Amphotericin B, antimonials, drug resistance, leishmaniasis, miltefocine, paromomycin
Leishmaniasis is a vector borne protozoan disease and it remains a major public health problem world‑wide. Lack of an effective vaccine and vector control program makes the chemotherapy as the primary tool for leishmaniasis. Antimonials were used as the first line of treatment for many years. Emergence of resistance against this drug has become a major concern. Literatures and studies published on anti‑leishmanial drug resistance, newer drug discovery for leishmanial resistance etc., in PubMed, Medline and Google search and reviewed thoroughly. Various newer drugs have been identified but, are in limited use because of high cost, toxicity, resistance etc., Recently, many newer mechanisms of drug resistance have been identified which may boost in future designing and development of drugs.
Latin America and Central Asia. The prevalence of leishmaniasis has been reported approximately 12 million cases with an annual mortality rate of 60,000.[2] Around 2 million new cases of leishmaniasis are detected every year out of which 50,000 cases were diagnosed as VL.[2] More than 90% of these cases were reported from the five developing countries, i.e., Sudan, Brazil, Bangladesh, India (Bihar) and Nepal.[3] The disease is endemic in several other poor and developing countries; hence, now it is included in the list of the neglected tropical diseases. Around 200 million people from India are at risk estimating approximately 67% of the world’s risk population.[4] it is especially prevalent in Bihar (>90%), Uttar Pradesh, West Bengal and Jharkhand. Free availability of anti‑leishmanial drug in India increases the chances of misuse; thereby increases the emergence of drug resistance.[2] It was observed that 73% of total VL patients first consult to an unqualified medical practitioner, who may not have the exact knowledge about drug dosage, duration of intake etc., Irregular and incomplete intake of drug leads to progressive tolerance and significant contributor in development of drug resistance in India. Cost of the drug is also one of the major contributing factors in development of resistance. Among all the drugs, antimonials are the only one which can be affordable. Majority of patients unable to complete the full course of the other drugs leads to the development of resistance. In the other
INTRODUCTION Leishmaniasis is an important parasitic disease, caused by protozoa Leishmania. There are 21 Leishmania spp., prevalent world‑wide with the potential to cause human infection.[1] The disease presents with four major clinical manifestations (visceral leishmaniasis [VL], cutaneous leishmaniasis [CL], mucocutaneous leishmaniasis and post‑kalaazar dermal leishmaniasis [PKDL]). VL is the most serious presentation amongst all and may lead to death with lack of treatment. Leishmania donovani causes VL or kalaazar. It is transmitted by sandfly Plebotomus argentipes. The parasite exists in two stages: Amastigote or intracellular forms in man and promastigote or extracellular form in sandfly. It is endemic in many parts of the world such as Africa, Address for correspondence Dr. Sarita Mohapatra, Room No. 515, 5th Floor, College Building, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi - 110 029, India. E-mail: [email protected] Access this article online Quick Response Code:
Website: www.tropicalparasitology.org DOI: 10.4103/2229-5070.129142
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hand, >90% of CL cases are reported from Afghanistan, Iran, Brazil, Peru and Saudi Arabia. Increased incidence of human immunodeficiency virus (HIV) co‑infection, human migration and resettlement (especially areas where leishmaniasis is zoonotic) in recent years may cause a resurgence of the number of cases. Since there is no effective vaccine available, control of leishmaniasis is primarily depends on chemotherapy. Pentavalent antimonial remains the key drug for last several decades. During last 10‑15 years, resistance to antimonials has been reported from all over the world; particularly from Bihar (India).[5] The second line drugs for VL includes amphotericin B (Amp B) and pentamidine. Various oral medications such as miltefosine and fluconazole are also got approval for VL and CL patients, respectively.[2] These second line anti‑leshmanials are less popular in the developing countries because of high cost, side effects and the requirement of hospitalization. It suggests the need of newer drugs for better management of this condition. This review highlights the mechanism of resistance to anti‑leishmanial drugs, newer anti‑leishmanial drugs under development and strategies to preserve the efficacy of currently used drugs.
Professor Bramhachari first synthesized the pentavalent antimony and used as a chemotherapeutic agent in Indian VL patients.[7] Initially, a dosage of 10 mg/kg for 6‑10 days showed clinical cure rate of 90% in VL patients.[3] Subsequently, higher dosage with prolong duration (20 mg/kg for 30 days) was suggested owing to failure of the treatment.[3] Unfortunately, it could not prevent the emergence of resistance of antimonials. Rather, more resistant strains were selected out and reached to an epidemic dimension in Bihar (India). Rapid spread of resistant strains in India occurred because of the anthroponotic transmission. It was observed only 64% of new VL cases from Bihar were sensitive to antimonials in additional to 100% resistant cases from Sitamari and Darbhanga district.[8] Although it is banned in India, antimonials are used as the first‑line treatment in the endemic areas world‑wide. Sensitivity of antimonials toward different Leishmania spp. varies differently. It is observed that, Leishmania brasilensis is more sensitive in comparison Leishmania mexicana.[9] Host factors such as decreased drug uptake, increased efflux mechanism, reduced concentration inside the parasite, inhibition of drug activation, inactivation of active drug and gene amplification are some important mechanisms responsible for the development of resistance in this group. Thiol metabolism also plays an important role in developing resistance.[3,10] Thiol molecule increases the oxidative stress inside the macrophage preventing glutathione formation and reduction of pentavalent antimonials to trivalent form. Therefore, increased intracellular thiol levels are associated with high antimonial resistance. The role of ABC transporters such as P‑glycoprotein and multidrug resistance (MDR)‑related protein in the drug resistance is proven in laboratory isolates of Leishmania spp.[10] However, its role in the field isolates is still not clear.[10]
The classification of various anti‑leishmanial drugs and their mechanism of action have been described below [Table 1]. ANTIMONIALS Antimony remains the mainstay of treatment for leishmaniasis since last 60 years. The mechanism of action is not very clear. It is known that the pentavalent form is inactive against Leishmania spp.[6] It utilizes thiols from the parasite and host cell surface and gets reduced to the trivalent form inside the macrophage, thereby act on the amastigote forms of the parasite.[3] In 1920,
AMP B
Table 1: Classification of anti‑leishmanial drugs Drug
Amp B is a polyene antifungal agent extracted from the filamentous bacteria called Streptomyces nodusus. It is used as the second line drug in patients with leishmaniasis. It is available in two forms, i.e., plain Amp B, liposomal Amp B. The latter one is better tolerated and less toxic.[11] Its mechanism of action is multifaceted.[12] Amp B is a sterol loving agent. It binds with cholesterol and forms pores in the host cell membrane causing leakage of cellular content followed by cell death. It helps in generation of reactive oxygen free radical. These radicals subsequently cause damage to cell leading to cell death. Although, Amp B has been proven as a successful chemotherapeutic agent in the leishmania patients, there are few reports indicating its resistance. Emergence of resistance could be expected because of high frequency of use of Amp B in India. The mechanism of resistance is not very clear. Recently, an
Mechanism of action
Antimonials Sodium Stibogluconate Diamidine Pentamidine Antifungals Amphotericin B Ketoconazole Others Miltefosine Paromomycin Allopurinol
Unclear; probably by inhibition of -SH dependent enzymes Interacts with kinetoplast DNA, inhibits topoisomerase II, interferes with aerobic glycolysis Bind with ergosterol of cell membrane of parasites forming micopores and leakage of cellular content Inhibiting conversion of lanosterol to ergosterol; impairment of membrane function Trigger programmed cell death Action on ribosomes causing inhibition of protein synthesis Prototype of pyrazolopyrimidine, inhibits growth
SH: Sulph-hydryl, DNA: Deoxyribonucleic acid
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article from India has proven the development of Amp B resistance due to the molecular mechanism.[12] It was observed that, the sterols in the cell wall of the amastigote forms of the resistant strains were replaced by a precursor, cholesta 5,7,24‑trien‑3 β‑ol.[12] It might have resulted due to defective trans‑methylation of C‑24 molecule by S‑adenosyl‑L‑methioninie: C‑24‑Δ‑sterol methyltransferase (SCMT) enzyme. SCMT enzyme is classified as SCMT A and SCMT B. In resistant strains, transcripts of SCMT‑A is found to be absent with over expression of SCMT‑B. Absence of SCMT‑A is possibly responsible for the defective trans‑methylation. This alteration in the membrane composition leads to decreased binding and reduced uptake of Amp B into the cell. MDR1 gene in the ABC transporters of promastigotes is responsible for drug efflux mechanism and subsequently leads to resistance. [12] There is three‑fold increased expression of MDR1 genes observed in resistant strains in comparison to sensitive strains.[12] The resistant strains also showed up regulation reactive oxygen species (ROS) scavenging machinery inside the cell. The cumulative effect of all mechanisms leads decreased concentration of Amp B inside the cell conferring to its resistance.
It is active against several parasites. In 2002, it was first introduced as anti‑leishmanial drug in the form of PM sulphate.[22] Low cost, fewer side‑effects, better efficacy and shorter duration of administration make this drug popular and thought to be a candidate for the first line therapy for VL patients.[23‑26] It belongs to the aminoglycoside group of antibiotic; hence, the mechanism of action is by inhibition of protein synthesis. There are several clinical trials undergoing to know the efficacy results of this drug by different routes. However, there is a likely chance of acquiring resistance with PM monotherapy. To combat these problems, newer formulations like PM loaded with albumin microsphere and PM with liposome have come up exhibiting better results.[27] NEWER DEVELOPMENTS The following newer compounds are in different stages of drug development and preclinical trials. The in vitro efficacy of these compounds has been shown in various animal studies. 2‑substituted quinoline 2‑substituted quinoline is a medicinal plant derivative, shows excellent activity against the new world CL.[28] Significant action against L. donovani has been observed in BALB/c mouse.[29] It is one of the most active quinoline against promastigote and amastigote forms of L. infantum and L. amazonensis.[29] In vitro activity of this compound against L. donovani found to be more efficacious in comparison to miltefosin and sitamaquine.[30] It does not possess in vitro antiplasmocidal or antitoxoplasmic activity.
MILTEFOSINE Miltefosine (hexadecylphosphocholine) is the first oral drug exhibiting 94% cure rate in VL patients.[5,13] It had shown good results against antimony resistant VL and PKDL cases.[14,15] Hence, in India, it is proposed to be the first‑line drug in the kalaazar elimination program.[16,17] The mechanism of action of this drug is unclear. It binds with the cell membrane, gets internalized by the help of two membrane proteins, i.e., L. donovani miltefosine transporter (LdMT) and L. donovani Ros3 (LdRos3).[18] It deranges the alkyl‑lipid metabolism of the parasite and cause apoptotic cell death. However, because of anthroponotic transmission in Indian subcontinent; misuse of the drug and its longer half‑life are the two factors that alarms acquiring of quick resistance to this drug.[19] Recently, there are reports of miltefosine resistant cases from Nepal.[20] The proposed mechanism of resistance was inactivation of genes responsible for drug uptake, i.e., LdMT and LdRos3.[21] In an Indian study, four‑point mutation was noticed showing variable drug response to miltefosine.[19] However, no significant genomic difference was observed between the genes of LdMT and LdRos3 between the sensitive and resistant strains. Hence, it is likely that, several other factors are also responsible for the mechanism of resistance of miltefosine apart from point mutation.
8‑aminoquinolines It is an antiprotozoal drug originally introduced as an antimalarial drug. Recently, phase II trial in India and Kenya showed its potency against L. donovani.[31] It causes apoptosis such as death of the parasite by chromatin fragmentation, enhanced reactive oxygen production, elevation of intracellular Ca +2 ion. [32] Recently, it is suggested to be considered as a candidate for combination therapy causing less toxicity and therapeutic failure. DRUGS TARGETING METABOLIC PATHWAY New anti‑leishmanial drug can be designed and developed targeting the metabolic pathways and biochemical structures of the parasite. Protein kinases are the key regulatory proteins and major target of metabolic pathway of Leishmania spp.[29] Among the various kinases, mitogen‑activated protein kinase, L. mexicana mitogen activated protein kinases‑1 (LmxMPK‑1), LmxMPK‑2 are found to be
PAROMOMYCIN PM is a broad spectrum antibiotic extracted from the bacterial spp. Streptomyces rimosus var. paromomycinus. Jan 2014 | Volume 4 | Issue 1 |
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essential for the survival of amastigotes inside the host and pathogenesis.[33] There are different libraries available, which one can screen and differentiate the parasite specific kinase from the human kinases. The above information can be utilized for the better optimization and designing of new drug. Among different cyclin dependent kinases, Cdc2‑related kinase‑3 (CRK‑3) observed to be the most potent and present in the amastigote form of L. donovani.[34,35] Another new inhibitor named as indirubin has been proven to be highly potent and active against L. donovani.[35] Its mechanism of action is linked with the CRK‑3 and other protein kinases.
HIV and kalaazar co‑infection HIV co‑infection in VL patients remains a major challenge for therapeutic management. These groups of patients develop early resistance and may show treatment failure or relapse of the disease with a rate of 0‑85%.[40] Treatment of these co‑infections is not very clear and varies from country to country depending upon the policy. Some follow treatment of antiretroviral therapy followed by anti‑leishmanial therapy, whereas few follow maintenance therapy with Amp B.[40] However, many trials on protease inhibitor for the drug dosage, efficacy and drug concentration are going on currently to evaluate the action against Leishmania species.[41]
ROLE OF INTERFERON GAMMA
STRATEGIES TO COMBAT THE DRUG RESISTANCE AND PRESERVE THE EFFICACY OF AVAILABLE DRUGS
In VL cases, the amastigote forms quench cholesterol from the cell membrane of macrophage during their intracellular stay; thereby making defective antigen presentation function.[36] This also interferes in the signaling of the IFNγ receptor oligomerization. Exogenous supply of cholesterol not only reinstates the receptor but also restores the IFNγ level; which is more host related than the parasite.[36] Hence, cholesterol liposomal formulation of IFNγ is a newly emerging therapeutic option in both drug sensitive and resistant cases, which enhances the macrophage mediated killing.
In addition to the pharmacologic factors, a number of host factors are responsible for the emergence and spread of drug resistance. These include improper monitoring of drug resistance, diagnostic methods, lack of compliance, drug availability and affordability, drug quality, limited drug distribution, limited access to peripheral health care facility for early treatment etc., Therefore, to prevent further emergence and spread of drug resistance and to preserve the efficacy of currently available drugs, the following strategies should be followed: • To determine drug resistance improved phenotypic and genotypic methods with good sensitivity should be developed and used • There is a need of development of good diagnostic tests, which can monitor the drug response as well as therapeutic outcome of the patient • Guideline based management should be introduced and hence that proper selection of anti‑leishmanials will be done • Directly observed therapies should be implicated to increase compliance • Drug affordability should be improved by joining the pharmaceutical companies with World Health Organization or Non‑Governmental Organizations • Continuous drug availability to the different health care facilities should be done to ensure the successful control of the disease • Strict rules for avoidance of suboptimal use or misuse of anti‑leishmanial drugs should be implemented and maintained at the national and peripheral level • Large scale control trials should be conducted to evaluate the safety and efficacy of combined regimens.
COMBINATION OF DRUGS Combination drug regimen for the treatment of VL is come into knowledge to combat the drug resistance developed by monotherapy. It can potentially broaden the spectrum, increase the activity of the drug by additive or synergistic action, decrease the duration and dosage, reduces the side effects and thereby reduces the cost of treatment and the emergence of drug resistance. Among the anti‑leishmanials, miltefosine and paramomycin were found appropriate for combination therapy because of less interference with other drugs. Recently, a randomized control trial was carried out in East Africa for the treatment of VL comparing PM 20 mg/kg/day for 21 days monotherapy with PM and sodium stibogluconate combination (PM 15 mg/kg/day and SSG 20 mg/kg/day for 17 day) and SSG (30 mg/kg/day for 30 days) alone. The 17 day combination regimen found equally efficacious and safer in comparison to 30 days regimen.[37] A phase III randomized control trial has been planned to observe the safety and efficacy of miltefosine alone, miltefosine with liposomal Amp B versus SSG with liposomal Amp B in primary VL patients in East Africa.[38] Recently, techniques are available to screen the action of the drugs; thereby detecting the drug resistance.[39] These methods also screen the natural compounds in the endemic region with the available libraries and would be able to discover new drugs. Tropical Parasitology
CONCLUSION The treatment of leishmaniasis still relies on very few drugs which are toxic, expensive and difficult to administer. Emergence of drug resistance along with lack 7
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of standard molecular markers for its detection makes the situation worse. Care must be taken to prevent the emergence and spread of drug resistance by proper understanding the mechanism of resistance, monitoring the drug use and its response. By understanding the resistance mechanism, many intracellular targets can be exploited, which will provide clues for designing newer drugs. Several large scale trials based on combination therapy going on, which may be extrapolated into successful management of leishmaniasis. Despite good knowledge on the epidemiology leishmaniasis, it still remains uncontrollable. Hence, efforts should be made to develop newer drugs which should be cheap, less toxic and easy to administer.
as an effective choice in the treatment of post‑kala‑azar dermal leishmaniasis. Br J Dermatol 2011;165:411‑4. 16. WHO. Expert Committee on Regional Strategic framework for Elimination of Kalaazar from the South‑East Region (2005‑2015). New Delhi: WHO Regional Office South‑East Asia;2005. 17. Joshi A, Narain JP, Prasittisuk C, Bhatia R, Hashim J. Can visceral leishmaniasis be eliminated from Asia?. J Vector Borne Dis 2008;45:105‑111. 18. Maltezou HC. Drug resistance in visceral leishmaniasis. J Biomed Biotechnol 2010;2010:617521. 19. Bhandari V, Kulshrestha A, Deep DK, Stark O, Prajapati VK, Ramesh V, et al. Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala‑azar dermal leishmaniasis. PLoS Negl Trop Dis 2012;6:e1657. 20. Pandey K, Pun SB, Pandey BD. Relapse of kala‑azar after use of multiple drugs: A case report and brief review of literature. Indian J Med Microbiol 2012;30:227‑9. 21. S e i f e r t K , M a t u S , J a v i e r P é r e z ‑Vi c t o r i a F, Castanys S, Gamarro F, Croft SL. Characterisation of Leishmania donovani promastigotes resistant to hexadecylphosphocholine (miltefosine). Int J Antimicrob Agents 2003;22:380‑7. 22. Williams D, Mullen AB, Baillie AJ, Carter KC. Comparison of the efficacy of free and non‑ionic‑surfactant vesicular formulations of paromomycin in a murine model of visceral leishmaniasis. J Pharm Pharmacol 1998;50:1351‑6. 23. Jha TK, Olliaro P, Thakur CP, Kanyok TP, Singhania BL, Singh IJ, et al. Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India. BMJ 1998;316:1200‑5. 24. Olliaro PL, Guerin PJ, Gerstl S, Haaskjold AA, Rottingen JA, Sundar S. Treatment options for visceral leishmaniasis: A systematic review of clinical studies done in India, 1980‑2004. Lancet Infect Dis 2005;5:763‑74. 25. Sundar S, Agrawal N, Arora R, Agarwal D, Rai M, Chakravarty J. Short‑course paromomycin treatment of visceral leishmaniasis in India: 14‑day vs 21‑day treatment. Clin Infect Dis 2009;49:914‑8. 26. Castro C, Macêdo V, Silva‑Vergara ML, Cuba C, Silveira CA, Carvalho E, et al. Effectiveness of aminosidine sulphate in severe visceral leishmaniasis, resistant to the treatment with pentavalent antimony. Rev Soc Bras Med Trop 1995;28:273‑7. 27. Wiwanitkit V. Interest in paromomycin for the treatment of visceral leishmaniasis (kala‑azar). Ther Clin Risk Manag 2012;8:323‑8. 28. Fournet A, Barrios AA, Muñoz V, Hocquemiller R, Cavé A, Bruneton J. 2‑substituted quinoline alkaloids as potential antileishmanial drugs. Antimicrob Agents Chemother 1993;37:859‑63. 29. Seifert K. Structures, targets and recent approaches in anti‑leishmanial drug discovery and development. Open Med Chem J 2011;5:31‑9. 30. Loiseau PM, Gupta S, Verma A, Srivastava S, Puri SK, Sliman F, et al. In vitro activities of new 2‑substituted quinolines against Leishmania donovani. Antimicrob Agents Chemother 2011;55:1777‑80. 31. Jha TK, Sundar S, Thakur CP, Felton JM, Sabin AJ, Horton J. A phase II dose‑ranging study of sitamaquine for the treatment of visceral leishmaniasis in India. Am J Trop Med Hyg 2005;73:1005‑11.
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Singh S. New developments in diagnosis of leishmaniasis. Indian J Med Res 2006;123:311‑30. 2. Croft SL, Sundar S, Fairlamb AH. Drug resistance in leishmaniasis. Clin Microbiol Rev 2006;19:111‑26. 3. Singh N. Drug resistance mechanisms in clinical isolates of Leishmania donovani. Indian J Med Res 2006;123:411‑22. 4. Chappuis F, Sundar S, Hailu A, Ghalib H, Rijal S, Peeling RW, et al. Visceral leishmaniasis: What are the needs for diagnosis, treatment and control? Nat Rev Microbiol 2007;5:873‑82. 5. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 2002;347:1739‑46. 6. Ouellette M, Ward S. Drug resistance in parasites. In: Marr J, Nielsen T, Komuniecki R, editors. Molecular Medical Parasitology. New York: Academic Press; 2002. p. 395‑430. 7. Bramhachari UN. Treatise on Kalaazar. London, UK: J. Bale Sons Danielsson; 1928. 8. Mishra M, Biswas UK, Jha DN, Khan AB. Amphotericin versus pentamidine in antimony‑unresponsive kala‑azar. Lancet 1992;340:1256‑7. 9. Navin TR, Arana BA, Arana FE, Berman JD, Chajón JF. Placebo‑controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J Infect Dis 1992;165:528‑34. 10. Haldar AK, Sen P, Roy S. Use of antimony in the treatment of leishmaniasis: Current status and future directions. Mol Biol Int 2011;2011:571242. 11. Sundar S, Gupta LB, Rastogi V, Agrawal G, Murray HW. Short‑course, cost‑effective treatment with amphotericin B‑fat emulsion cures visceral leishmaniasis. Trans R Soc Trop Med Hyg 2000;94:200‑4. 12. Purkait B, Kumar A, Nandi N, Sardar AH, Das S, Kumar S, et al. Mechanism of amphotericin B resistance in clinical isolates of Leishmania donovani. Antimicrob Agents Chemother 2012;56:1031‑41. 13. WHO. Expert Committee on Control of the Leishmaniasis. Geneva WHO Technical Report Series;2010. 14. Sundar S, Kumar K, Chakravarty J, Agrawal D, Agrawal S, Chhabra A, et al. Cure of antimony‑unresponsive Indian post‑kala‑azar dermal leishmaniasis with oral miltefosine. Trans R Soc Trop Med Hyg 2006;100:698‑700. 15. Ramesh V, Katara GK, Verma S, Salotra P. Miltefosine Jan 2014 | Volume 4 | Issue 1 |
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32. Carvalho L, Luque‑ Ortega JR, López‑Martín C, Castanys S, Rivas L, Gamarro F. The 8‑aminoquinoline analogue sitamaquine causes oxidative stress in Leishmania donovani promastigotes by targeting succinate dehydrogenase. Antimicrob Agents Chemother 2011;55:4204‑10. 33. Wiese M. Leishmania MAP kinases – Familiar proteins in an unusual context. Int J Parasitol 2007;37:1053‑62. 34. Grant KM, Dunion MH, Yardley V, Skaltsounis AL, Marko D, Eisenbrand G, et al. Inhibitors of Leishmania mexicana CRK3 cyclin‑dependent kinase: Chemical library screen and antileishmanial activity. Antimicrob Agents Chemother 2004;48:3033‑42. 35. Xingi E, Smirlis D, Myrianthopoulos V, Magiatis P, Grant KM, Meijer L, et al. 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. Int J Parasitol 2009;39:1289‑303. 36. Sen S, Roy K, Mukherjee S, Mukhopadhyay R, Roy S. Restoration of IFNγR subunit assembly, IFNγ signaling and parasite clearance in Leishmania donovani infected macrophages: Role of membrane cholesterol. PLoS Pathog 2011;7:e1002229. 37. Musa A, Khalil E, Hailu A, Olobo J, Balasegaram M,
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Omollo R, et al. Sodium stibogluconate (SSG) and paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: A randomised controlled trial. PLoS Negl Trop Dis 2012;6:e1674. 38. Omollo R, Alexander N, Edwards T, Khalil EA, Younis BM, Abuzaid AA, et al. Safety and efficacy of miltefosine alone and in combination with sodium stibogluconate and liposomal amphotericin B for the treatment of primary visceral leishmaniasis in East Africa: Study protocol for a randomized controlled trial. Trials 2011;12:166. 39. Siqueira‑Neto JL, Song OR, Oh H, Sohn JH, Yang G, Nam J, et al. Antileishmanial high‑throughput drug screening reveals drug candidates with new scaffolds. PLoS Negl Trop Dis 2010;4:e675. 40. Croft SL, Olliaro P. Leishmaniasis chemotherapy – Challenges and opportunities. Clin Microbiol Infect 2011;17:1478‑83. 41. van Griensven J, Diro E, Lopez‑Velez R, Boelaert M, Lynen L, Zijlstra E, et al. HIV‑1 protease inhibitors for treatment of visceral leishmaniasis in HIV‑co‑infected individuals. Lancet Infect Dis 2013;13:251‑9. How to cite this article: Mohapatra S. Drug resistance in leishmaniasis: Newer developments. Trop Parasitol 2014;4:4-9. Source of Support: Nil. Conflict of Interest: None declared. DOA: 11-11-2013, DOP: 20-03-2014
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Drug resistance in leishmaniasis: Newer developments Sarita Mohapatra Department of Microbiology, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
ABSTRACT
KEY WORDS
Amphotericin B, antimonials, drug resistance, leishmaniasis, miltefocine, paromomycin
Leishmaniasis is a vector borne protozoan disease and it remains a major public health problem world‑wide. Lack of an effective vaccine and vector control program makes the chemotherapy as the primary tool for leishmaniasis. Antimonials were used as the first line of treatment for many years. Emergence of resistance against this drug has become a major concern. Literatures and studies published on anti‑leishmanial drug resistance, newer drug discovery for leishmanial resistance etc., in PubMed, Medline and Google search and reviewed thoroughly. Various newer drugs have been identified but, are in limited use because of high cost, toxicity, resistance etc., Recently, many newer mechanisms of drug resistance have been identified which may boost in future designing and development of drugs.
Latin America and Central Asia. The prevalence of leishmaniasis has been reported approximately 12 million cases with an annual mortality rate of 60,000.[2] Around 2 million new cases of leishmaniasis are detected every year out of which 50,000 cases were diagnosed as VL.[2] More than 90% of these cases were reported from the five developing countries, i.e., Sudan, Brazil, Bangladesh, India (Bihar) and Nepal.[3] The disease is endemic in several other poor and developing countries; hence, now it is included in the list of the neglected tropical diseases. Around 200 million people from India are at risk estimating approximately 67% of the world’s risk population.[4] it is especially prevalent in Bihar (>90%), Uttar Pradesh, West Bengal and Jharkhand. Free availability of anti‑leishmanial drug in India increases the chances of misuse; thereby increases the emergence of drug resistance.[2] It was observed that 73% of total VL patients first consult to an unqualified medical practitioner, who may not have the exact knowledge about drug dosage, duration of intake etc., Irregular and incomplete intake of drug leads to progressive tolerance and significant contributor in development of drug resistance in India. Cost of the drug is also one of the major contributing factors in development of resistance. Among all the drugs, antimonials are the only one which can be affordable. Majority of patients unable to complete the full course of the other drugs leads to the development of resistance. In the other
INTRODUCTION Leishmaniasis is an important parasitic disease, caused by protozoa Leishmania. There are 21 Leishmania spp., prevalent world‑wide with the potential to cause human infection.[1] The disease presents with four major clinical manifestations (visceral leishmaniasis [VL], cutaneous leishmaniasis [CL], mucocutaneous leishmaniasis and post‑kalaazar dermal leishmaniasis [PKDL]). VL is the most serious presentation amongst all and may lead to death with lack of treatment. Leishmania donovani causes VL or kalaazar. It is transmitted by sandfly Plebotomus argentipes. The parasite exists in two stages: Amastigote or intracellular forms in man and promastigote or extracellular form in sandfly. It is endemic in many parts of the world such as Africa, Address for correspondence Dr. Sarita Mohapatra, Room No. 515, 5th Floor, College Building, Vardhaman Mahavir Medical College and Safdarjung Hospital, New Delhi - 110 029, India. E-mail: [email protected] Access this article online Quick Response Code:
Website: www.tropicalparasitology.org DOI: 10.4103/2229-5070.129142
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hand, >90% of CL cases are reported from Afghanistan, Iran, Brazil, Peru and Saudi Arabia. Increased incidence of human immunodeficiency virus (HIV) co‑infection, human migration and resettlement (especially areas where leishmaniasis is zoonotic) in recent years may cause a resurgence of the number of cases. Since there is no effective vaccine available, control of leishmaniasis is primarily depends on chemotherapy. Pentavalent antimonial remains the key drug for last several decades. During last 10‑15 years, resistance to antimonials has been reported from all over the world; particularly from Bihar (India).[5] The second line drugs for VL includes amphotericin B (Amp B) and pentamidine. Various oral medications such as miltefosine and fluconazole are also got approval for VL and CL patients, respectively.[2] These second line anti‑leshmanials are less popular in the developing countries because of high cost, side effects and the requirement of hospitalization. It suggests the need of newer drugs for better management of this condition. This review highlights the mechanism of resistance to anti‑leishmanial drugs, newer anti‑leishmanial drugs under development and strategies to preserve the efficacy of currently used drugs.
Professor Bramhachari first synthesized the pentavalent antimony and used as a chemotherapeutic agent in Indian VL patients.[7] Initially, a dosage of 10 mg/kg for 6‑10 days showed clinical cure rate of 90% in VL patients.[3] Subsequently, higher dosage with prolong duration (20 mg/kg for 30 days) was suggested owing to failure of the treatment.[3] Unfortunately, it could not prevent the emergence of resistance of antimonials. Rather, more resistant strains were selected out and reached to an epidemic dimension in Bihar (India). Rapid spread of resistant strains in India occurred because of the anthroponotic transmission. It was observed only 64% of new VL cases from Bihar were sensitive to antimonials in additional to 100% resistant cases from Sitamari and Darbhanga district.[8] Although it is banned in India, antimonials are used as the first‑line treatment in the endemic areas world‑wide. Sensitivity of antimonials toward different Leishmania spp. varies differently. It is observed that, Leishmania brasilensis is more sensitive in comparison Leishmania mexicana.[9] Host factors such as decreased drug uptake, increased efflux mechanism, reduced concentration inside the parasite, inhibition of drug activation, inactivation of active drug and gene amplification are some important mechanisms responsible for the development of resistance in this group. Thiol metabolism also plays an important role in developing resistance.[3,10] Thiol molecule increases the oxidative stress inside the macrophage preventing glutathione formation and reduction of pentavalent antimonials to trivalent form. Therefore, increased intracellular thiol levels are associated with high antimonial resistance. The role of ABC transporters such as P‑glycoprotein and multidrug resistance (MDR)‑related protein in the drug resistance is proven in laboratory isolates of Leishmania spp.[10] However, its role in the field isolates is still not clear.[10]
The classification of various anti‑leishmanial drugs and their mechanism of action have been described below [Table 1]. ANTIMONIALS Antimony remains the mainstay of treatment for leishmaniasis since last 60 years. The mechanism of action is not very clear. It is known that the pentavalent form is inactive against Leishmania spp.[6] It utilizes thiols from the parasite and host cell surface and gets reduced to the trivalent form inside the macrophage, thereby act on the amastigote forms of the parasite.[3] In 1920,
AMP B
Table 1: Classification of anti‑leishmanial drugs Drug
Amp B is a polyene antifungal agent extracted from the filamentous bacteria called Streptomyces nodusus. It is used as the second line drug in patients with leishmaniasis. It is available in two forms, i.e., plain Amp B, liposomal Amp B. The latter one is better tolerated and less toxic.[11] Its mechanism of action is multifaceted.[12] Amp B is a sterol loving agent. It binds with cholesterol and forms pores in the host cell membrane causing leakage of cellular content followed by cell death. It helps in generation of reactive oxygen free radical. These radicals subsequently cause damage to cell leading to cell death. Although, Amp B has been proven as a successful chemotherapeutic agent in the leishmania patients, there are few reports indicating its resistance. Emergence of resistance could be expected because of high frequency of use of Amp B in India. The mechanism of resistance is not very clear. Recently, an
Mechanism of action
Antimonials Sodium Stibogluconate Diamidine Pentamidine Antifungals Amphotericin B Ketoconazole Others Miltefosine Paromomycin Allopurinol
Unclear; probably by inhibition of -SH dependent enzymes Interacts with kinetoplast DNA, inhibits topoisomerase II, interferes with aerobic glycolysis Bind with ergosterol of cell membrane of parasites forming micopores and leakage of cellular content Inhibiting conversion of lanosterol to ergosterol; impairment of membrane function Trigger programmed cell death Action on ribosomes causing inhibition of protein synthesis Prototype of pyrazolopyrimidine, inhibits growth
SH: Sulph-hydryl, DNA: Deoxyribonucleic acid
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article from India has proven the development of Amp B resistance due to the molecular mechanism.[12] It was observed that, the sterols in the cell wall of the amastigote forms of the resistant strains were replaced by a precursor, cholesta 5,7,24‑trien‑3 β‑ol.[12] It might have resulted due to defective trans‑methylation of C‑24 molecule by S‑adenosyl‑L‑methioninie: C‑24‑Δ‑sterol methyltransferase (SCMT) enzyme. SCMT enzyme is classified as SCMT A and SCMT B. In resistant strains, transcripts of SCMT‑A is found to be absent with over expression of SCMT‑B. Absence of SCMT‑A is possibly responsible for the defective trans‑methylation. This alteration in the membrane composition leads to decreased binding and reduced uptake of Amp B into the cell. MDR1 gene in the ABC transporters of promastigotes is responsible for drug efflux mechanism and subsequently leads to resistance. [12] There is three‑fold increased expression of MDR1 genes observed in resistant strains in comparison to sensitive strains.[12] The resistant strains also showed up regulation reactive oxygen species (ROS) scavenging machinery inside the cell. The cumulative effect of all mechanisms leads decreased concentration of Amp B inside the cell conferring to its resistance.
It is active against several parasites. In 2002, it was first introduced as anti‑leishmanial drug in the form of PM sulphate.[22] Low cost, fewer side‑effects, better efficacy and shorter duration of administration make this drug popular and thought to be a candidate for the first line therapy for VL patients.[23‑26] It belongs to the aminoglycoside group of antibiotic; hence, the mechanism of action is by inhibition of protein synthesis. There are several clinical trials undergoing to know the efficacy results of this drug by different routes. However, there is a likely chance of acquiring resistance with PM monotherapy. To combat these problems, newer formulations like PM loaded with albumin microsphere and PM with liposome have come up exhibiting better results.[27] NEWER DEVELOPMENTS The following newer compounds are in different stages of drug development and preclinical trials. The in vitro efficacy of these compounds has been shown in various animal studies. 2‑substituted quinoline 2‑substituted quinoline is a medicinal plant derivative, shows excellent activity against the new world CL.[28] Significant action against L. donovani has been observed in BALB/c mouse.[29] It is one of the most active quinoline against promastigote and amastigote forms of L. infantum and L. amazonensis.[29] In vitro activity of this compound against L. donovani found to be more efficacious in comparison to miltefosin and sitamaquine.[30] It does not possess in vitro antiplasmocidal or antitoxoplasmic activity.
MILTEFOSINE Miltefosine (hexadecylphosphocholine) is the first oral drug exhibiting 94% cure rate in VL patients.[5,13] It had shown good results against antimony resistant VL and PKDL cases.[14,15] Hence, in India, it is proposed to be the first‑line drug in the kalaazar elimination program.[16,17] The mechanism of action of this drug is unclear. It binds with the cell membrane, gets internalized by the help of two membrane proteins, i.e., L. donovani miltefosine transporter (LdMT) and L. donovani Ros3 (LdRos3).[18] It deranges the alkyl‑lipid metabolism of the parasite and cause apoptotic cell death. However, because of anthroponotic transmission in Indian subcontinent; misuse of the drug and its longer half‑life are the two factors that alarms acquiring of quick resistance to this drug.[19] Recently, there are reports of miltefosine resistant cases from Nepal.[20] The proposed mechanism of resistance was inactivation of genes responsible for drug uptake, i.e., LdMT and LdRos3.[21] In an Indian study, four‑point mutation was noticed showing variable drug response to miltefosine.[19] However, no significant genomic difference was observed between the genes of LdMT and LdRos3 between the sensitive and resistant strains. Hence, it is likely that, several other factors are also responsible for the mechanism of resistance of miltefosine apart from point mutation.
8‑aminoquinolines It is an antiprotozoal drug originally introduced as an antimalarial drug. Recently, phase II trial in India and Kenya showed its potency against L. donovani.[31] It causes apoptosis such as death of the parasite by chromatin fragmentation, enhanced reactive oxygen production, elevation of intracellular Ca +2 ion. [32] Recently, it is suggested to be considered as a candidate for combination therapy causing less toxicity and therapeutic failure. DRUGS TARGETING METABOLIC PATHWAY New anti‑leishmanial drug can be designed and developed targeting the metabolic pathways and biochemical structures of the parasite. Protein kinases are the key regulatory proteins and major target of metabolic pathway of Leishmania spp.[29] Among the various kinases, mitogen‑activated protein kinase, L. mexicana mitogen activated protein kinases‑1 (LmxMPK‑1), LmxMPK‑2 are found to be
PAROMOMYCIN PM is a broad spectrum antibiotic extracted from the bacterial spp. Streptomyces rimosus var. paromomycinus. Jan 2014 | Volume 4 | Issue 1 |
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essential for the survival of amastigotes inside the host and pathogenesis.[33] There are different libraries available, which one can screen and differentiate the parasite specific kinase from the human kinases. The above information can be utilized for the better optimization and designing of new drug. Among different cyclin dependent kinases, Cdc2‑related kinase‑3 (CRK‑3) observed to be the most potent and present in the amastigote form of L. donovani.[34,35] Another new inhibitor named as indirubin has been proven to be highly potent and active against L. donovani.[35] Its mechanism of action is linked with the CRK‑3 and other protein kinases.
HIV and kalaazar co‑infection HIV co‑infection in VL patients remains a major challenge for therapeutic management. These groups of patients develop early resistance and may show treatment failure or relapse of the disease with a rate of 0‑85%.[40] Treatment of these co‑infections is not very clear and varies from country to country depending upon the policy. Some follow treatment of antiretroviral therapy followed by anti‑leishmanial therapy, whereas few follow maintenance therapy with Amp B.[40] However, many trials on protease inhibitor for the drug dosage, efficacy and drug concentration are going on currently to evaluate the action against Leishmania species.[41]
ROLE OF INTERFERON GAMMA
STRATEGIES TO COMBAT THE DRUG RESISTANCE AND PRESERVE THE EFFICACY OF AVAILABLE DRUGS
In VL cases, the amastigote forms quench cholesterol from the cell membrane of macrophage during their intracellular stay; thereby making defective antigen presentation function.[36] This also interferes in the signaling of the IFNγ receptor oligomerization. Exogenous supply of cholesterol not only reinstates the receptor but also restores the IFNγ level; which is more host related than the parasite.[36] Hence, cholesterol liposomal formulation of IFNγ is a newly emerging therapeutic option in both drug sensitive and resistant cases, which enhances the macrophage mediated killing.
In addition to the pharmacologic factors, a number of host factors are responsible for the emergence and spread of drug resistance. These include improper monitoring of drug resistance, diagnostic methods, lack of compliance, drug availability and affordability, drug quality, limited drug distribution, limited access to peripheral health care facility for early treatment etc., Therefore, to prevent further emergence and spread of drug resistance and to preserve the efficacy of currently available drugs, the following strategies should be followed: • To determine drug resistance improved phenotypic and genotypic methods with good sensitivity should be developed and used • There is a need of development of good diagnostic tests, which can monitor the drug response as well as therapeutic outcome of the patient • Guideline based management should be introduced and hence that proper selection of anti‑leishmanials will be done • Directly observed therapies should be implicated to increase compliance • Drug affordability should be improved by joining the pharmaceutical companies with World Health Organization or Non‑Governmental Organizations • Continuous drug availability to the different health care facilities should be done to ensure the successful control of the disease • Strict rules for avoidance of suboptimal use or misuse of anti‑leishmanial drugs should be implemented and maintained at the national and peripheral level • Large scale control trials should be conducted to evaluate the safety and efficacy of combined regimens.
COMBINATION OF DRUGS Combination drug regimen for the treatment of VL is come into knowledge to combat the drug resistance developed by monotherapy. It can potentially broaden the spectrum, increase the activity of the drug by additive or synergistic action, decrease the duration and dosage, reduces the side effects and thereby reduces the cost of treatment and the emergence of drug resistance. Among the anti‑leishmanials, miltefosine and paramomycin were found appropriate for combination therapy because of less interference with other drugs. Recently, a randomized control trial was carried out in East Africa for the treatment of VL comparing PM 20 mg/kg/day for 21 days monotherapy with PM and sodium stibogluconate combination (PM 15 mg/kg/day and SSG 20 mg/kg/day for 17 day) and SSG (30 mg/kg/day for 30 days) alone. The 17 day combination regimen found equally efficacious and safer in comparison to 30 days regimen.[37] A phase III randomized control trial has been planned to observe the safety and efficacy of miltefosine alone, miltefosine with liposomal Amp B versus SSG with liposomal Amp B in primary VL patients in East Africa.[38] Recently, techniques are available to screen the action of the drugs; thereby detecting the drug resistance.[39] These methods also screen the natural compounds in the endemic region with the available libraries and would be able to discover new drugs. Tropical Parasitology
CONCLUSION The treatment of leishmaniasis still relies on very few drugs which are toxic, expensive and difficult to administer. Emergence of drug resistance along with lack 7
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of standard molecular markers for its detection makes the situation worse. Care must be taken to prevent the emergence and spread of drug resistance by proper understanding the mechanism of resistance, monitoring the drug use and its response. By understanding the resistance mechanism, many intracellular targets can be exploited, which will provide clues for designing newer drugs. Several large scale trials based on combination therapy going on, which may be extrapolated into successful management of leishmaniasis. Despite good knowledge on the epidemiology leishmaniasis, it still remains uncontrollable. Hence, efforts should be made to develop newer drugs which should be cheap, less toxic and easy to administer.
as an effective choice in the treatment of post‑kala‑azar dermal leishmaniasis. Br J Dermatol 2011;165:411‑4. 16. WHO. Expert Committee on Regional Strategic framework for Elimination of Kalaazar from the South‑East Region (2005‑2015). New Delhi: WHO Regional Office South‑East Asia;2005. 17. Joshi A, Narain JP, Prasittisuk C, Bhatia R, Hashim J. Can visceral leishmaniasis be eliminated from Asia?. J Vector Borne Dis 2008;45:105‑111. 18. Maltezou HC. Drug resistance in visceral leishmaniasis. J Biomed Biotechnol 2010;2010:617521. 19. Bhandari V, Kulshrestha A, Deep DK, Stark O, Prajapati VK, Ramesh V, et al. Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala‑azar dermal leishmaniasis. PLoS Negl Trop Dis 2012;6:e1657. 20. Pandey K, Pun SB, Pandey BD. Relapse of kala‑azar after use of multiple drugs: A case report and brief review of literature. Indian J Med Microbiol 2012;30:227‑9. 21. S e i f e r t K , M a t u S , J a v i e r P é r e z ‑Vi c t o r i a F, Castanys S, Gamarro F, Croft SL. Characterisation of Leishmania donovani promastigotes resistant to hexadecylphosphocholine (miltefosine). Int J Antimicrob Agents 2003;22:380‑7. 22. Williams D, Mullen AB, Baillie AJ, Carter KC. Comparison of the efficacy of free and non‑ionic‑surfactant vesicular formulations of paromomycin in a murine model of visceral leishmaniasis. J Pharm Pharmacol 1998;50:1351‑6. 23. Jha TK, Olliaro P, Thakur CP, Kanyok TP, Singhania BL, Singh IJ, et al. Randomised controlled trial of aminosidine (paromomycin) v sodium stibogluconate for treating visceral leishmaniasis in North Bihar, India. BMJ 1998;316:1200‑5. 24. Olliaro PL, Guerin PJ, Gerstl S, Haaskjold AA, Rottingen JA, Sundar S. Treatment options for visceral leishmaniasis: A systematic review of clinical studies done in India, 1980‑2004. Lancet Infect Dis 2005;5:763‑74. 25. Sundar S, Agrawal N, Arora R, Agarwal D, Rai M, Chakravarty J. Short‑course paromomycin treatment of visceral leishmaniasis in India: 14‑day vs 21‑day treatment. Clin Infect Dis 2009;49:914‑8. 26. Castro C, Macêdo V, Silva‑Vergara ML, Cuba C, Silveira CA, Carvalho E, et al. Effectiveness of aminosidine sulphate in severe visceral leishmaniasis, resistant to the treatment with pentavalent antimony. Rev Soc Bras Med Trop 1995;28:273‑7. 27. Wiwanitkit V. Interest in paromomycin for the treatment of visceral leishmaniasis (kala‑azar). Ther Clin Risk Manag 2012;8:323‑8. 28. Fournet A, Barrios AA, Muñoz V, Hocquemiller R, Cavé A, Bruneton J. 2‑substituted quinoline alkaloids as potential antileishmanial drugs. Antimicrob Agents Chemother 1993;37:859‑63. 29. Seifert K. Structures, targets and recent approaches in anti‑leishmanial drug discovery and development. Open Med Chem J 2011;5:31‑9. 30. Loiseau PM, Gupta S, Verma A, Srivastava S, Puri SK, Sliman F, et al. In vitro activities of new 2‑substituted quinolines against Leishmania donovani. Antimicrob Agents Chemother 2011;55:1777‑80. 31. Jha TK, Sundar S, Thakur CP, Felton JM, Sabin AJ, Horton J. A phase II dose‑ranging study of sitamaquine for the treatment of visceral leishmaniasis in India. Am J Trop Med Hyg 2005;73:1005‑11.
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32. Carvalho L, Luque‑ Ortega JR, López‑Martín C, Castanys S, Rivas L, Gamarro F. The 8‑aminoquinoline analogue sitamaquine causes oxidative stress in Leishmania donovani promastigotes by targeting succinate dehydrogenase. Antimicrob Agents Chemother 2011;55:4204‑10. 33. Wiese M. Leishmania MAP kinases – Familiar proteins in an unusual context. Int J Parasitol 2007;37:1053‑62. 34. Grant KM, Dunion MH, Yardley V, Skaltsounis AL, Marko D, Eisenbrand G, et al. Inhibitors of Leishmania mexicana CRK3 cyclin‑dependent kinase: Chemical library screen and antileishmanial activity. Antimicrob Agents Chemother 2004;48:3033‑42. 35. Xingi E, Smirlis D, Myrianthopoulos V, Magiatis P, Grant KM, Meijer L, et al. 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. Int J Parasitol 2009;39:1289‑303. 36. Sen S, Roy K, Mukherjee S, Mukhopadhyay R, Roy S. Restoration of IFNγR subunit assembly, IFNγ signaling and parasite clearance in Leishmania donovani infected macrophages: Role of membrane cholesterol. PLoS Pathog 2011;7:e1002229. 37. Musa A, Khalil E, Hailu A, Olobo J, Balasegaram M,
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Omollo R, et al. Sodium stibogluconate (SSG) and paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: A randomised controlled trial. PLoS Negl Trop Dis 2012;6:e1674. 38. Omollo R, Alexander N, Edwards T, Khalil EA, Younis BM, Abuzaid AA, et al. Safety and efficacy of miltefosine alone and in combination with sodium stibogluconate and liposomal amphotericin B for the treatment of primary visceral leishmaniasis in East Africa: Study protocol for a randomized controlled trial. Trials 2011;12:166. 39. Siqueira‑Neto JL, Song OR, Oh H, Sohn JH, Yang G, Nam J, et al. Antileishmanial high‑throughput drug screening reveals drug candidates with new scaffolds. PLoS Negl Trop Dis 2010;4:e675. 40. Croft SL, Olliaro P. Leishmaniasis chemotherapy – Challenges and opportunities. Clin Microbiol Infect 2011;17:1478‑83. 41. van Griensven J, Diro E, Lopez‑Velez R, Boelaert M, Lynen L, Zijlstra E, et al. HIV‑1 protease inhibitors for treatment of visceral leishmaniasis in HIV‑co‑infected individuals. Lancet Infect Dis 2013;13:251‑9. How to cite this article: Mohapatra S. Drug resistance in leishmaniasis: Newer developments. Trop Parasitol 2014;4:4-9. Source of Support: Nil. Conflict of Interest: None declared. DOA: 11-11-2013, DOP: 20-03-2014
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