Leishmaniasis: Current status of available drugs and new potential drug targets

Abstract

The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericin B, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

“…Such works highlighted the potential of some AGs for treating nonsense mediated human genetic disorders by encoding near-cognate tRNA molecules at premature termination codon positions (5)(6)(7). Other studies have shown that specific AGs can be used as alternative treatments for infections caused by human parasitic protozoa such as trypanosomiasis, giardiasis, amoebiasis and leishmaniasis (8)(9)(10)(11)(12). Nevertheless, despite the great potential use of AGs for additional therapeutic purposes, very little information is available regarding their molecular mechanisms of action in eukaryotes.…”

“…It affects millions of people worldwide, appearing mainly in tropical and subtropical areas (12). The parasite is transmitted by sandflies and, depending on the type of disease, can be fatal if untreated.…”

Caracterización bioquímica de la enzima bifuncional dihidrofolato reductasa-timidilato sintasa de Leishmania (Viannia) y su evaluación como blanco molecular

“…DHFR is a key enzyme in folate metabolism, linked to the production of thymidine (12). In several species of protozoa, the catalytic activities for the enzymes DHFR and TS reside on a single polypeptide chain, constituting a bifunctional DHFR-TS enzyme (14,15).…”

“…The ORF of the DHFR-TS has been amplified, cloned and sequenced; the sequences showed a high degree of conservation, both at nucleotide (96%) and protein (90%) level. The bifunctional enzyme has been thus considered as a potential drug target (12,15). Nevertheless, there are no reports on the bifunctional enzyme on Le.…”

“…A limited number of drugs is available and each has various shortcomings. Traditional antileishmanial systemic agents such as antimonials, pentamidine and amphotericin are limited by severe toxic side effects, emerging drug resistance and their requirement for parenteral administration (8)(9)(10)(11)(12). Newer agents such as oral miltefosine have shown efficacy and tolerability, although the efficacy of this compound has not been demonstrated for all Leishmania species.…”