Exploiting Knowledge on Leishmania Drug Resistance to Support the Quest for New Drugs (original) (raw)
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Leishmaniasis refers to a diverse spectrum of clinical syndromes caused by infection with protozoan parasites of the genus <em>Leishmania</em>. They are widely distributed across the tropical, subtropical, and temperate regions in 88 countries, 72 of which are in developing areas of the world. The diagnosis and treatment of the different syndromes produced by these parasites are particularly difficult in developed and non-endemic countries because of poor knowledge of clinical symptoms, diagnostic possibilities, and available treatment options. This article highlights the biology, life cycle, diagnostic, chemotherapeutic, and strategies to control Leishmaniasis.
Advances in Development of New Treatment for Leishmaniasis
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Leishmaniasis is a neglected infectious disease caused by several different species of protozoan parasites of the genus Leishmania. Current strategies to control this disease are mainly based on chemotherapy. Despite being available for the last 70 years, leishmanial chemotherapy has lack of efficiency, since its route of administration is difficult and it can cause serious side effects, which results in the emergence of resistant cases. The medical-scientific community is facing difficulties to overcome these problems with new suitable and efficient drugs, as well as the identification of new drug targets. The availability of the complete genome sequence of Leishmania has given the scientific community the possibility of large-scale analysis, which may lead to better understanding of parasite biology and consequent identification of novel drug targets. In this review we focus on how high-throughput analysis is helping us and other groups to identify novel targets for chemotherapeut...
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Human leishmaniasis is a complex skin infection that imposes a heavy burden on many tropical and subtropical developing countries and is caused by over 20 species of Leishmaniaparasite and they are transmitted by several sand y species. The disease is mainly associated with dis guring scars and major social stigma during infection. Disease severity appears to depend on many factors, including parasite species, host, endemic area, socioeconomic status, and access to health facilities. Despite the many studies that have been conducted on current and new treatments, the treatment outcomes of leishmaniasis remain controversial, possibly because of the knowledge gaps that still exist. Varying responses to current leishmania treatments have become a major drawback in disease control. The lack of information on critical analyses of the results of such studies is a barrier to overall understanding. Based on the currently available literature on treatment outcomes, we discuss the most effective doses, drug susceptibilities/resistances, and treatment failures of Leishmania for monotherapy and combination therapy. This review focuses on the available therapies for leishmaniasis caused by different Leishmania species, with insights into their species-speci c e cacy, which will inform the selection of drugs for the treatment and control of leishmaniasis. For this aim, the search was conducted in electronic databases of PubMed, Scopus, web of sciences and Google scholar. The speci c search medical subject headings (MeSH) terms include "
Current Status of Existing and Emerging Chemotherapy and Drug Resistance Mechanisms in Leishmania
International Journal of Advance Research and Innovative Ideas in Education, 2017
Leishmaniasis is a well known fatal disease that is caused by the protozoan species belonging to the genus Leishmania. The causative organism is transmitted through female sandflies. It is considered as a neglected tropical disease and targeted for the worldwide elimination by the World Health Organization. It is the major cause of significant morbidity and mortality in several countries of the world. Leishmania parasites cause a wide spectrum of human and animal infections ranging from the life threatening visceral disease to the disfiguring mucosal and cutaneous forms of the disease. Currently, the control of the disease totally relies on chemotherapy, as the vaccine is still under the process of development. Organic pentavalentantimonials [Sb (V)] have been the first-line drugs for the treatment of Leishmaniasis for the last seven decades. Alternatively, Amphotericin B, pentamidine and miltefosine can be used for the treatment of leishmaniasis. However, these drugs have serious l...
Importance of secondary screening with clinical isolates for anti-leishmania drug discovery
Scientific Reports, 2018
The growing drug resistance (DR) raises major concerns for the control of visceral leishmaniasis (VL), a neglected disease lethal in 95 percent of the cases if left untreated. Resistance has rendered antimonials (SSG) obsolete in the Indian Sub-Continent (ISC) and the first miltefosine-resistant Leishmania donovani were isolated. New chemotherapeutic options are needed and novel compounds are being identified by high-throughput screening (HTS). HTS is generally performed with old laboratory strains such as LdBOB and we aimed here to validate the activity of selected compounds against recent clinical isolates. In this academic/industrial collaboration, 130 compounds from the GSK "Leishbox" were screened against one SSG-sensitive and one SSG-resistant strain of L. donovani recently isolated from ISC patients, using an intracellular assay of L. donovani-infected THP1-derived macrophages. We showed that only 45% of the compounds were active in both clinical isolates and LdBOB. There were also different compound efficiencies linked to the SSG susceptibility background of the strains. In addition, our results suggested that the differential susceptibility profiles were chemical series-dependent. In conclusion, we demonstrate the potential value of including clinical isolates (as well as resistant strains) in the HTS progression cascade. Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania 1. It occurs in several parts of the world under different clinical forms, the most severe being visceral leishmaniasis (VL), also known as kala-azar; a systemic illness that is lethal if left untreated. Every year, 200,000-400,000 new cases of VL happen, due to parasites of the L. donovani complex, essentially in India, Nepal, Bangladesh, Sudan, Ethiopia and Brazil, with a mortality estimated at 10% 1. In the Indian sub-continent (ISC) a regional program aiming for the elimination of VL (Kala-Azar elimination program or KAEP) is currently running, based on two major pillars, vector control and chemotherapy 2. Currently, there are only few therapeutic options for leishmaniasis and they have various drawbacks 3. Pentavalent antimonials (SSG) were used for decades, but they are limited by toxicity and treatment failure (TF) primarily caused by resistant parasites. This led to the progressive withdrawal of SSG in the Indian Sub-Continent (ISC) since 2005 4. At that time, SSG was replaced by Miltefosine (MIL), the first oral treatment available for leishmaniasis 5. However the use of MIL is being threatened by the alarming rise of TF in the ISC 6 and recently, the first MIL-resistant strains were detected in the field 7. The development of a liposomal form of Amphotericin B (Ambisome) has reduced its toxicity but its availability to patients is restricted by high costs 8. Preferential pricing agreement increased access to Ambisome and a single-dose treatment is now used as the first line treatment in the ISC 9. Combination therapies are used as an alternative, but this strategy might be questioned, when one of the composing drug is starting to fail (like MIL); in addition, experimental work has shown that L. donovani resistant to combined drugs could easily be selected in vitro 10. Currently there are no other drugs available, and new compounds, formulations or combinations are urgently needed. High-throughput screening (HTS) is an efficient way of identifying active compounds 11,12 able to eliminate the parasite without affecting the host. Whole-cell phenotypic HTS is used for anti-leishmania drug discovery because of the low number of molecular targets well characterized and validated 13. The parasite life stage used
Leishmaniasis: treatment, drug resistance and emerging therapies
Expert Opinion on Orphan Drugs, 2018
Introduction: Leishmaniasis is one of the most neglected tropical infectious diseases in the world. Emergence of drug resistance and toxicity and high cost of the available drugs with lack of new antileishmanial drugs highlight the need to search for newer molecules with antileishmanial activities. Areas covered: This article describes the currently available antileishmanial drugs and their risk of developing resistance and discusses newer therapies. These include oral lipid-based formulations of amphotericin B, use of different drug delivery systems, and quinolone derivativesnaphthoquinone, buparvaquone, etc. Expert opinion: There are only a handful of antileishmanial drugs, and even fewer in the pipeline. Guidelinebased treatment, with proper selection of antileishmanial compound, should be practiced. Combination therapy should be used preferably to prevent or delay drug resistance. As most patients with PKDL (post-kalaazar dermal leishmaniasis) are asymptomatic, it is important that shorter regimens are developed, which will encourage patients to opt for complete treatment. Pharmaceutical industry and "not for profit' organizations should be encouraged to enhance the efforts in finding clinically effective antileishmanial drugs.
Understanding Human Leishmaniasis:The Need for an Integrated Approach
Encyclopedia of Infectious Diseases
is 12 million people. Most of the affected countries are in the tropics and subtropics: more than 90% of the world's cases of visceral leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil (Fig. 6.2), 90% of all cases of mucocutaneous leishmaniasis (Fig. 6.3) occur in Bolivia, Brazil, and Peru, whereas 90% of all cases of cutaneous leishmaniasis (Fig. 6.3) occur in Afghanistan, Brazil, Iran, Peru, Saudi Arabia, and Syria (for further detail, see http://www.who.int/leishmaniasis/en/). 6.1.2 The Players in Leishmaniasis Leishmania parasites are responsible for cutaneous forms as well as visceral forms of the disease. Healing or progression of this infection is related to the genetic and immune status of the host, the virulence and pathogenicity of different species and strains of Leishmania, and the vector involved. The hosts can be humans but also rodents, dogs, and other mammals [16,307], and great diversity of immune response exists depending on the host considered (see Section 6.4 for details). Similarly, within 500 known phlebotomine species, only 31 have been positively identified as vectors of the Leishmania pathogenic species and 43 as probable vectors [181]. Among them, some vectors such as Phlebotomus Phlebotomus papatasi and P. Paraphlebotomus sergenti can only be 87