title: Chemotherapeutic potential of 17-AAG against cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis.
abstract: BACKGROUND
  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 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.
  
  
  RESULTS
  Exposure 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.
  
  
  CONCLUSIONS
  17-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.
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil.
authors.forename: Diego M
authors.initials: DM
authors.lastname: Santos
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil.
authors.forename: Antonio L O A
authors.initials: AL
authors.lastname: Petersen
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil.
authors.forename: Fabiana S
authors.initials: FS
authors.lastname: Celes
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil; Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia (iii-INCT), Salvador, Bahia, Brazil.
authors.forename: Valeria M
authors.initials: VM
authors.lastname: Borges
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil.
authors.forename: Patricia S T
authors.initials: PS
authors.lastname: Veras
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Bahia, Brazil; Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia (iii-INCT), Salvador, Bahia, Brazil.
authors.forename: Camila I
authors.initials: CI
authors.lastname: de Oliveira
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D015850:Interleukin-6 / Q000096:biosynthesis; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D007892:Leishmania braziliensis / Q000187:drug effects* / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000276:immunology; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D047029:Lactams, Macrocyclic; D014409:Tumor Necrosis Factor-alpha; C112765:tanespimycin; D000666:Amphotericin B