Inhibitory activity of pentacyano(isoniazid)ferrate(II), IQG-607, against promastigotes and amastigotes forms of Leishmania braziliensis.

Camila F Amorim,Luiz A Basso,Diógenes Santiago Santos,Pablo Machado,Valnês S Rodrigues-Junior,Natália B Carvalho,Kenia Pissinate,Edgar M Carvalho,Luiza Galina,Maria M Campos,Nathalia D M Sperotto,Yara M Traub-Csekö

doi:10.1371/journal.pone.0190294

Abstract

M. tuberculosis and parasites of the genus Leishmania present the type II fatty acid biosynthesis system (FASII). The pentacyano(isoniazid)ferrate(II) compound, named IQG-607, inhibits the enzyme 2-trans-enoyl-ACP(CoA) reductase from M. tuberculosis, a key component in the FASII system. Here, we aimed to evaluate the inhibitory activity of IQG-607 against promastigote and amastigote forms of Leishmania (Viannia) braziliensis isolated from patients with different clinical forms of L. braziliensis infection, including cutaneous, mucosal and disseminated leishmaniasis. Importantly, IQG-607 inhibited the proliferation of three different isolates of L. braziliensis promastigotes associated with cutaneous, mucosal and disseminated leishmaniasis. The IC50 values for IQG-607 ranged from 32 to 75 μM, for these forms. Additionally, IQG-607 treatment decreased the proliferation of intracellular amastigotes in infected macrophages, after an analysis of the percentage of infected cells and the number of intracellular parasites/100 cells. IQG-607 reduced from 58% to 98% the proliferation of L. braziliensis from cutaneous, mucosal and disseminated strains. Moreover, IQG-607 was also evaluated regarding its potential toxic profile, by using different cell lines. Cell viability of the lineages Vero, HaCat and HepG2 was significantly reduced after incubation with concentrations of IQG-607 higher than 2 mM. Importantly, IQG-607, in a concentration of 1 mM, did not induce DNA damage in HepG2 cells, when compared to the untreated control group. Future studies will confirm the mechanism of action of IQG-607 against L. braziliensis.

Highlights

The American tegumentary leishmaniasis (ATL) is considered one of the most important infections among all the neglected tropical diseases [1], with an extremely high morbidity rate [2, 3]
To evaluate whether IQG-607 was able to inhibit the growth of L. braziliensis promastigotes, the three different strains associated with cutaneous, mucosal and disseminated cutaneous of leishmaniasis were cultivated in the presence of the test drug
IQG-607 inhibited the proliferation of L. braziliensis promastigotes of all clinical forms of leishmaniasis in a similar way (Fig 1)

Summary

Introduction

The American tegumentary leishmaniasis (ATL) is considered one of the most important infections among all the neglected tropical diseases [1], with an extremely high morbidity rate [2, 3]. It is endemic in 98 countries and 5 continents, with approximately 1.5 million cases occurring per year [4]. AMB is the most effective drug for the treatment of leishmaniasis but its adverse reactions, mainly kidney injury, limit its use [14,15,16]. The discovery of new effective drugs against leishmaniasis with low cost and reduced toxic profile is highly desirable [17, 18]

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