<div><p>Background</p><p>Leishmaniasis 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 <i>L. (L.) amazonensis</i> infection <i>in vitro</i>. Herein, we expand the current knowledge on the leishmanicidal activity of 17-AAG against cutaneous leishmaniasis, employing an experimental model of infection with <i>L. (V.) braziliensis</i>.</p><p>Methodology/Principal findings</p><p>Exposure of axenic <i>L. (V.) braziliensis</i> promastigotes to 17-AAG resulted in direct dose-dependent parasite killing. These results were extended to <i>L. (V.) braziliensis</i>-infected macrophages, an effect that was dissociated from the production of nitric oxide (NO), superoxide (O<sup>−2</sup>) or inflammatory mediators such as TNF-α, IL-6 and MCP-1. The leishmanicidal effect was then demonstrated <i>in vivo</i>, employing BALB/c mice infected with <i>L. braziliensis</i>. 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.</p><p>Conclusion/Significance</p><p>17-AAG effectively inhibited the growth of <i>L. braziliensis</i>, both <i>in vitro</i> and <i>in vivo</i>. Given the chronicity of <i>L. (V.) braziliensis</i> infection and its association with mucocutaneous leishmaniasis, 17-AAG can be envisaged as a new chemotherapeutic alternative for cutaneous Leishmaniasis.</p></div
