Abstract
BackgroundLeishmaniasis remains a worldwide public health problem. The limited therapeutic options, drug toxicity and reports of resistance, reinforce the need for the development of new treatment options. Previously, we showed that 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a Heat Shock Protein 90 (HSP90)-specific inhibitor, reduces L. (L.) amazonensis infection in vitro. Herein, we expand the current knowledge on the leishmanicidal activity of 17-AAG against cutaneous leishmaniasis, employing an experimental model of infection with L. (V.) braziliensis.Methodology/Principal findingsExposure of axenic L. (V.) braziliensis promastigotes to 17-AAG resulted in direct dose-dependent parasite killing. These results were extended to L. (V.) braziliensis-infected macrophages, an effect that was dissociated from the production of nitric oxide (NO), superoxide (O−2) or inflammatory mediators such as TNF-α, IL-6 and MCP-1. The leishmanicidal effect was then demonstrated in vivo, employing BALB/c mice infected with L. braziliensis. In this model, 17-AAG treatment resulted in smaller skin lesions and parasite counts were also significantly reduced. Lastly, 17-AAG showed a similar effect to amphotericin B regarding the ability to reduce parasite viability.Conclusion/Significance17-AAG effectively inhibited the growth of L. braziliensis, both in vitro and in vivo. Given the chronicity of L. (V.) braziliensis infection and its association with mucocutaneous leishmaniasis, 17-AAG can be envisaged as a new chemotherapeutic alternative for cutaneous Leishmaniasis.
Highlights
Leishmaniasis is a widespread group of parasitic diseases caused by protozoa of the genus Leishmania, that is transmitted by the bite of female sand flies
We evaluated the ability of 17-AAG to kill Leishmania (Viannia) braziliensis parasites, a species that causes both cutaneous and mucocutaneous Leishmaniasis in Brazil
Heat Shock Protein 90 (HSP90) is associated with important biological processes; inhibition of this molecule interferes with parasite survival and, it can be exploited as a chemotherapeutic target
Summary
Leishmaniasis is a widespread group of parasitic diseases caused by protozoa of the genus Leishmania, that is transmitted by the bite of female sand flies. About 12 million people are at risk of leishmaniasis and there are an estimated 1.5–2 million new cases each year [1]. (V.) braziliensis to persist within lesion scars after spontaneous or chemotherapy-mediated healing and to its ability to metastasize to the nasal mucosal [3,4]. In this case, extensive tissue destruction is observed, resulting from the potent cell-mediated immune response triggered by parasite replication [5]. We expand the current knowledge on the leishmanicidal activity of 17-AAG against cutaneous leishmaniasis, employing an experimental model of infection with L. We expand the current knowledge on the leishmanicidal activity of 17-AAG against cutaneous leishmaniasis, employing an experimental model of infection with L. (V.) braziliensis
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