Drug Resistance in Leishmania Parasites: Consequences, Molecular Mechanisms and Possible Treatments
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In contrast to malaria, Leishmania does not have a classical folate de novo biosynthetic pathway. There is evidence that radioactive biopterin can be converted into folates 5 , but radioactive PABA is not incorporated into folates 48 and none of the sulphonamides tested has shown activity against Leishmania 64 ; Leishmania thus rely heavily on import under standard conditions. Leishmania cells without measurable folate transport grow perfectly well under standard laboratory conditions. Their folates are therefore obtained by either other routes of entry or by increased de novo synthesis.
Recent work has permitted the isolation of the biopterin transporter BT1 50 ; Nevertheless, the mutation occurred in the amplified gene and not in the chromosomal single copy gene as for malaria parasite. The main function of PTR1 is to salvage oxidized pterins; a secondary function is reduction of folates.
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The PTR1 therefore serves as an alternative route for the synthesis of reduced folates and its amplification will lead to MTX resistance 59 ; We have also observed that modulation in PTR1 activity in T. Folates and antifolates are polyglutamylated and the level of polyglutamylation is an important determinant of antifolate therapy efficacy in mammalian cells We have recently investigated the levels of polyglutamylation in Leishmania cells and found that the level of polyglutamylation indeed appears to influence antifolate response in Leishmania A.
This would be an example of drug modification that would decrease the efficacy of a drug. This has not yet been observed, however.
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The drug in clinical use against Leishmania infection consists in pentavalent antimony but it is generally agreed that the active form of the metal is the trivalent form. Reduction of the metal may take place either in the parasites, in the macrophage or in both. Some studies suggest that reduction takes place in the host cell 72 while others suggest that it occurs in the parasite If the latter is the case, a loss of reductase activity could lead to drug resistance. This hypothesis received support from a study showing that L. Leishmania cells selected for resistance to trivalent antimony or trivalent arsenicals had increased levels of trypanothione TSH 58 ; 52 ; The TSH is the major reduced thiol of Leishmania cells and is composed of a N 1 ,N 8 bisglutathione spermidine conjugate Transport experiments indicated that active efflux of the metal outside the cell was increased in resistant cells 20 and biochemical characterization suggested that this efflux system recognized the metal conjugated to TSH This synergistic interaction is observed, however, only into a specific genetic background.
Thus, PGPA would confer resistance by sequestration of the conjugated metal.
Although some of the mechanisms of metal resistance induced in vitro in the lab are starting to be understood in Leishmania , it remains to be seen whether similar mechanisms operate in field isolates. Resistance to suramin is rare and not a problem in clinical practice. Resistance to the pentavalent arsenical melarsoprol does occur 53 , which leaves no alternatives for treatment.
Resistance to melarsoprol and other arsenical drugs has been studied mostly in vitro. Resistant parasites lack the P2 transporter suggesting that resistance to arsenicals can be the result of loss of uptake The nucleoside transporter gene from T.
It remains to be seen how widespread mutations in P2 occur in trypanosomiasis patients infected with T. The common structural feature for recognition is likely to reside in the melamine and benzamidine moieties of the two classes of drugs 3. P2 is not the only route, however, by which pentamidine can enter T.
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The drug is active against late stage T. The ODC activity and stability of T. The mechanisms of eflornithine resistance in clinical strains of T. This high level of ornithine was proposed to compete with eflornithine for ODC, hence leading to sufficient biosynthesis of polyamines and of trypanothione 7 ; Bona fide drug resistance in common worm infections is not yet widespread in human medicine, but as it is in veterinary medicine 36 the potential for resistance is important.
Benzimidazoles, which bind to tubulin, are used against veterinary parasites. Levamisole acts as a cholinergic antagonist in nematodes but the resistance mechanism to this class of drugs is yet unknown. A reduction in the number of receptors has nonetheless been proposed as one possible mechanism for resistance Finally, both the mechanism of action and resistance mechanisms if any of the antischistosomal drug praziquantel are unknown Drug resistance complicates the treatment of parasitic infections.
Studies of drug resistance can help to find strategies to increase the efficacy or the life span of the few drugs available. Once the resistance mechanisms are understood, specific tests can be developed for the genotypic diagnosis of resistance.
Biochemical and molecular mechanisms of drug resistance in parasites
They have already been in use for detecting antifolate 4 ; 60 and chloroquine resistance 23 in malaria and tests to detect resistance determinants in other parasites are likely to emerge once resistance mechanisms are better understood. Our ability to detect resistance can be useful to determine the prevalence of resistance in specific geographical regions or can also prevent the use of useless and toxic drugs for patients infected with resistant parasites. It may also limit the use of last resort drugs only when absolutely required while dealing with resistant parasites.
The understanding of resistance mechanisms can also lead to new strategies for chemotherapeutic interventions. The advent of miltefosine as a new antileishmanial drug introduces APLs as putative novel drugs for the treatment of leishmaniasis. In addition, because of the numerous studies reported on the antitumor action of these compounds, it could be envisaged that the insight acquired for their antitumor action might be of use in the treatment of leishmaniasis.
As stated above miltefosine is a member of a series of synthetic lipids structurally related and known collectively as APLs, which in turn can be classified in two major categories [ 31 ]: a the alkyl ether phospholipids AEPs , widely referred to collectively as alkyl-lysophospholipid analogs ALPs , containing ether bonds in the glycerol backbone of the phospholipid, as exemplified by 1- O -octadecyl O -methyl- rac -glycerophosphocholine ETOCH 3 ; edelfosine Figure 1 ; b and the alkylphosphocholines APCs , lacking the glycerol backbone and formed by a simple long-chain alcohol esterified to a phosphobase, as exemplified by hexadecylphosphocholine HPC; miltefosine Figure 1.
All of these APLs show low rates of metabolism both in vitro and in vivo. APLs were initially shown to elicit actions on the immune system and to kill cancer cells [ 31 , 33 , 35 ]. The first studies of the antiprotozoal activity of APLs in the s against Tetrahymena pyriformis [ 36 ] and L. APLs have been reported to be effective against different Leishmania species, including L. In , Croft et al.
Drug Resistance in Leishmania Parasites | Angus & Robertson
Within APLs, edelfosine has been considered as the long-standing prototype of these compounds, and recent evidences have unveiled part of its mechanism of action as a promising antitumor drug. Another APL named perifosine, a miltefosine analog, is currently in clinical trials for different types of cancer. Thus, the insights gained in the last years on both the mechanism of action of APLs as antitumor agents, especially edelfosine, and the clinical experience acquired with some of these compounds, particularly miltefosine and perifosine, constitute an invaluable source of information for the putative use of APLs as antiparasitic drugs, as well as for the development of novel APL-related compounds as antileishmanial drugs.