Review articleLeishmania treatment and prevention: Natural and synthesized drugs
Graphical abstract
Introduction
Leishmaniasis is a parasitic infection caused by the protozoan Leishmania parasites, which are transmitted by the bite of infected female phlebotomine sand flies. Leishmania has two life cycles: intracellular amastigotes in the mammalian host, and the promastigotes in the fly [1,2].
Leishmaniasis is endemic in more than 90 countries worldwide and at least 13 million people are estimated to be infected [3,4]. The diagnosis of leishmaniasis is limited by variations and subclinical manifestations of the disease. Leishmania mainly affects poor people in Africa, Asia, and Latin America; and is associated with malnutrition, population displacement, poor housing, and a weak immune system. Leishmaniasis currently threatens 350 million men, women, and children in 88 countries around the world [5,6]. An estimated 0.9 to 1.3 million new cases and 20,000 to 30,000 deaths are predicted to occur annually due to leishmaniasis [5,6].
There are four main forms of leishmaniasis: visceral (also known as kala-azar, and is considered as the most serious form of the disease), cutaneous (the most common), mucocutaneous, and post kala-azar [[7], [8], [9], [10]]. Cutaneous leishmaniasis (CL) is a neglected clinical form of public health importance. It is caused by several species of Leishmania, mainly L. tropica, L. major, L. amazonesis and L. Mexicana. The CL may be a Zoonotic cutaneous leishmaniasis (ZCL) or an anthroponotic cutaneous leishmaniasis (ACL) [[11], [12], [13]]. The other type of leishmaniasis is Mucocutaneous leishmaniasis, also known as “Espundia”, which is caused mainly by the species L. vianniabraziliensis. L. vianniapanamensis and L. amazonesis have also been reported to affect mucosal tissues [12]. Visceral leishmaniasis (VL, Kala-azar) is a growing public health challenge that is manifested by L. donovani and L. infantum infections.
Leishmania donovani infections are restricted to the (sub-) tropics of Asia and Africa, where transmission is mostly anthroponotic, while L. infantum occurs in the drier parts of Latin America as well as in the Mediterranean region, with domestic dogs serving as the main reservoir host [[14], [15], [16], [17]]. Finally, post Kala-azar dermal leishmaniasis is caused by the protozoan parasite L. donovani and is the most clinically and scientifically intriguing form of the disease since it generally develops as a sequela after a patient's apparent successful cure from visceral leishmaniasis [18,19].
There are several known antileishmanial drugs currently available, such as amphotericin B, antimonials, sitamaquine, pentamidine, paromomycin, and miltefosine. Generally, antileishmanial drugs have immunomodulatory activity and can stimulate the innate immune system [20], but several drawbacks manifest during the treatment regimen have been recorded. Pentavalent antimonials have been used to be the predominant drug for treatment of VL. However, these drugs were found to be toxic and have adverse side effects that can lead to fatality [21]. Pentamidine has also been previously used in the treatment of VL. Despite its effectiveness in the treatment of pentavalent antimony-resistant VL, its use has decreased due to the route of administration (injection) and the toxic side effects associated with the drug [22].
Miltefosine was the first oral drug used for the treatment of visceral and cutaneous leishmaniasis but due to its teratogenicity, prolonged treatment regimen, and high resistance potential, its use has declined [23,24]. Amphotericin B (AmB) has high leishmanicidal activity and its use results in fewer treatment failures and relapses. However, it causes nephrotoxicity and requires parenteral administration, which has led to its rejection as a first-choice treatment [25,26]. The usefulness of sitamaquine also is limited due to its severe nephrotoxicity, which can result in kidney failure as well as its potential to cause methemoglobinemia [27]. Paromomycin is an old aminoglycoside antibiotic that has been recently approved for use in the treatment of leishmaniasis. Drug resistance development, as well as common side effects such as ototoxicity and liver dysfunction, have been common drawbacks with this drug [28,29].
Although the range of antileishmanial drugs has expanded, the currently available drugs do not meet the increasing requirements of managing infection in different patient populations since drug resistance and toxicity have been reported for all the currently available drugs [21,[30], [31], [32], [33], [34]]. However, a combination of treatments for visceral leishmaniasis has been shown to be more effective and safer to use as they were found to decrease the duration of therapy and reduce the emergence of drug-resistant parasites [[35], [36], [37], [38], [39], [40], [41]].
The objective of this review is to provide an update on natural drugs, their semisynthetic derivatives and synthesized agents that show leishmanicidal activity. Given the problem of resistance, we also emphasize the structure-functional aspects of some new potential targets that may provide a new approach in the field of antileishmanial therapy, as well as research on the development of an effective vaccine.
Section snippets
Herbal antileishmanial agents
According to the World Health Organisation (WHO), the plant kingdom is the only option for developing a therapeutic agent that has both a high safety profile and cost-effectiveness for several health problems (WHO, 2015). For example, Allium cepa and Azadirachta indica are used for the treatment of skin disorders [42], citrulluscolocynthis, buckwheat, and chamomile are useful in treating cardiovascular diseases [43], and Salvia, Valeriana, and Hypericum are used as antiprotozoal agents [44].
Synthesized antileishmanial agents
Various heterocyclic moieties, in either single or fused systems, possess antileishmanial properties (Table 2). This section of the review discusses some of these heterocyclic moieties. Fig. 3 and Fig. 4 provide examples of synthesized antileishmanial agents.
Antileishmanial potential targets
The main problems associated with the currently available antileishmanial drugs are their side effects and the tendency of the parasite to develop resistance on long-term. These problems are also the main drivers for the development of new drug discoveries [117]. A target-based drug discovery approach is a new strategy to improve antileishmanial treatment. This approach depends on the identification of new potential targets and validation through biochemical analysis [[118], [119], [120], [121]
Vaccination
The development of a Leishmania vaccine has proven to be a challenging task. An effective immune protection has not yet been established. This is may be due to a limited knowledge about parasite pathogenesis. The immune responses of leishmnasis are complex and unclear. Patients affected with Leishmania are susceptible to reinfection due to problems with the currently used drugs and the lack of a prophylactic medicine. Therefore, there is a crucial need to develop an effective vaccine exhibiting
Conclusions and future perspective
The need for new antileishmanial drugs continues to be an urgent target for researchers due to the toxicity, adverse effects and developed resistance to current treatments. Among the vaccines developed for Leishmania, leishmanization and HbR-DNA appear to be the most promising, but intensive evaluation of leishmanization against various types of Leishmania should be carried out and good safety records of these techniques should be established before widespread use is considered. Given that most
Financial & competing interests disclosure
The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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