Emerging targets for the development of novel antifungal therapeutics

Groll, Andreas H.; Lucca, Anthony J. De; Walsh, Thomas J.

doi:10.1016/s0966-842x(97)01206-7

Cited by 83 publications

(60 citation statements)

References 66 publications

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“…The ␤ glucans, besides contributing with chitin to the strength and shape of the cell wall, are known to be endowed with potent immunomodulatory activity (44) mediated by interaction with pattern recognition receptors on different cells (18,27,43) and represent attractive targets for antifungal chemotherapy (1). The ␤(1,3)-D-glucan inhibitor caspofungin has recently been described to be effective in treating aspergillosis in leukopenic mice (14).…”

Section: Discussionmentioning

confidence: 99%

Protection of Killer Antiidiotypic Antibodies against Early Invasive Aspergillosis in a Murine Model of Allogeneic T-Cell-Depleted Bone Marrow Transplantation

Cenci¹,

Mencacci²,

Spreca

et al. 2002

Infect Immun

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Antiidiotypic monoclonal antibodies (MAbs) representing the internal image of a yeast killer toxin (KT)have therapeutic potential against several fungal infections. The efficacy of KT MAbs against Aspergillus fumigatus was investigated in a mouse model of T-cell-depleted allogeneic bone marrow transplantation (BMT) with invasive pulmonary aspergillosis. Mice were highly susceptible to infection at 3 days post-BMT, when profound neutropenia was observed both in the periphery and in the lungs. Treatment with KT MAbs protected the mice from infection, as judged by the long-term survival and decreased pathology associated with inhibition of fungal growth and hyphal development in the lungs. In vitro, similar to polymorphonuclear neutrophils, KT MAbs significantly inhibited the hyphal development and metabolic activity of germinated Aspergillus conidia. These results indicate that mimicking the action of neutrophils could be a strategy through which KT MAbs exert therapeutic efficacy in A. fumigatus infections.Invasive fungal infections remain a major problem for bone marrow (BM) transplant (BMT) recipients (35,45). Mortality from opportunistic fungal infections exceeds 50% in most studies and has been reported to be as high as 95% in allogeneic BMT recipients with Aspergillus sp. infection, despite aggressive antifungal therapy (4).Studies in vitro and in animal models have indicated that the innate defenses are primarily responsible for the elimination of inhaled conidia from the lungs (10,13,19,38). Early fungal clearance is mediated by a dual phagocytic system involving both alveolar macrophages and recruited polymorphonuclear leukocytes capable of efficiently opposing fungal infectivity at the level of conidia or hyphal forms (37). However, the killing of phagocytosed conidia by mononuclear cells is a slow process that occurs with a low killing rate and depends on the immunocompetence of effector monocytes (19). Moreover, the finding that the conidiocidal activity of monocytes in both clinical disease and experimental chronic granulomatous disease is largely unaffected (26) reveals the unique importance of neutrophil activity against germinating conidia and hyphae in the control of aspergillosis.Human studies have shown that prolonged neutropenia is one of the most important factors predisposing to invasive aspergillosis (35,45). However, the efficacy of immunotherapies aimed at both shortening the duration of neutropenia and restoring neutrophil antifungal activity has been limited by problems associated with the transfusion therapy, including the still uncertain efficacy of colony-stimulating factors (34) and the limited persistence of the transfused cells (16). It appears that strategies aimed at keeping the infection in check until the recovery of adequate innate antifungal activity are needed for prompt handling of the fungus by the host.Recent studies have highlighted the therapeutic potential of killer antiidiotypic antibodies in several fungal infections (23). Antiidiotypes to a monoclonal antibody (MAb)...

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Section: Discussionmentioning

confidence: 99%

Protection of Killer Antiidiotypic Antibodies against Early Invasive Aspergillosis in a Murine Model of Allogeneic T-Cell-Depleted Bone Marrow Transplantation

Cenci¹,

Mencacci²,

Spreca

et al. 2002

Infect Immun

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“…Opportunistic infection can lead to the development of systemic candidosis which is often fatal in immunocompromised patients [1][2][3][4]. Existing therapies for systemic fungal infections rely on the use of polyene and azole anti-fungal drugs, such as nystatin and ketoconazole.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antimicrobial activity and chemotherapeutic potential of inorganic derivatives of 2-(4′-thiazolyl)benzimidazole{thiabendazole}: X-ray crystal structures of [Cu(TBZH)2Cl]Cl·H2O·EtOH and TBZH2NO3 (TBZH=thiabendazole)

Devereux¹,

McCann

Shea³

et al. 2004

Journal of Inorganic Biochemistry

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“…O Sp-3 inibiu em mesma concentração as espécies A. niger LM 05, T. inkin LM 067 e T. rubrum ATCC 1683. Estes dados de inibição são corroborados por outras literaturas que também realizaram pesquisa de novos compostos antimicrobianos através de triagem clássica de produtos naturais (Groll et al, 1998;Ujikawa, 2003). Na microdiluição, o grupo controle sem droga inibitória apresentou o resultado esperado com crescimento para todas as espécies, e o controle com a droga antifúngica padrão cetoconazol 50 μg/mL inibiu o crescimento das cepas T. inkin LM 067 e A. fumigatus ATCC 0406.…”

Section: Resultsunclassified

Atividade antifúngica e cinética de morte microbiana de extratos obtidos de Streptomyces spp. isolados de solos paraibanos

Oliveira¹,

Lima²,

Souza³

et al. 2010

Rev. bras. farmacogn.

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RESUMO:Foram coletadas sessenta e oito amostras em diferentes solos paraibanos, com o isolamento de quarenta e nove cepas de Streptomyces spp. Após triagem antimicrobiana, por meio da técnica de difusão em meio sólido com blocos de agar, foram preparados os extratos dos microrganismos produtores de metabólitos bioativos, respectivamente cepas SP1 e SP3, e em seguida avaliados quanto a atividade antifúngica frente a espécies de fungos filamentosos de origem clínica e ATCC. O antagonismo foi determinado através dos ensaios de difusão com discos em meio sólido, microdiluição e cinética de morte microbiana. Os halos de inibição obtidos a partir dos extratos Sp-1 e Sp-3 apresentaram efeito antagônico com valores superiores aos halos de inibição promovidos pela droga controle, frequentemente utilizada na terapêutica antifúngica. Os resultados das concentrações inibitórias mínimas na microdiluição foram expressivos com valores fungicidas variando entre 10 mg e 0,078125 mg. Na cinética de morte microbiana, as atividades dos extratos Sp-1 e Sp-3 resultaram em dados estatisticamente significativos frente às cepas testes.Unitermos: Streptomyces, extratos, atividade antifúngica, cinética.ABSTRACT: "Antifungal activity and kinetics of microbial death of extracts obtained from Streptomyces spp. isolated from paraibano soils". Sixty eight samples were collected in different soils of Paraiba, with the isolation of forty nine strains of Streptomyces spp. After screening antimicrobial followed the method of diffusion in solid medium with agar block, the extracts were prepared from microorganism producers of bioactive metabolites, respectively strains SP1 and SP3, and then evaluated for antifungal activity against strains of filamentous fungi of clinical origin and ATCC. The antagonism was determined through testing of diffusion disc in solid medium, microdilution and kinetics of microbial death. The inhibition zones obtained from extracts of Sp-1 and Sp-3 showed antagonistic effect with values greater than the halos of inhibition promoted by the drug control, often used in antifungal therapy. The results of minimum inhibitory concentrations in microdilution were significant with fungicide values ranging between 10 mg and 0.078125 mg. In the kinetics of microbial death, the activities of the extracts Sp-1 and Sp-3 resulted in statistically significant data front of strains tested.

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Emerging targets for the development of novel antifungal therapeutics

Cited by 83 publications

References 66 publications

Protection of Killer Antiidiotypic Antibodies against Early Invasive Aspergillosis in a Murine Model of Allogeneic T-Cell-Depleted Bone Marrow Transplantation

Protection of Killer Antiidiotypic Antibodies against Early Invasive Aspergillosis in a Murine Model of Allogeneic T-Cell-Depleted Bone Marrow Transplantation

Synthesis, antimicrobial activity and chemotherapeutic potential of inorganic derivatives of 2-(4′-thiazolyl)benzimidazole{thiabendazole}: X-ray crystal structures of [Cu(TBZH)2Cl]Cl·H2O·EtOH and TBZH2NO3 (TBZH=thiabendazole)

Atividade antifúngica e cinética de morte microbiana de extratos obtidos de Streptomyces spp. isolados de solos paraibanos

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