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Pesquisa : D08.811. [Categoria DeCS]
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[Au] Autor:Bublitz M; Kjellerup L; Cohrt KO; Gordon S; Mortensen AL; Clausen JD; Pallin TD; Hansen JB; Fuglsang AT; Dalby-Brown W; Winther AL
[Ad] Endereço:Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
[Ti] Título:Tetrahydrocarbazoles are a novel class of potent P-type ATPase inhibitors with antifungal activity.
[So] Source:PLoS One;13(1):e0188620, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have identified a series of tetrahydrocarbazoles as novel P-type ATPase inhibitors. Using a set of rationally designed analogues, we have analyzed their structure-activity relationship using functional assays, crystallographic data and computational modeling. We found that tetrahydrocarbazoles inhibit adenosine triphosphate (ATP) hydrolysis of the fungal H+-ATPase, depolarize the fungal plasma membrane and exhibit broad-spectrum antifungal activity. Comparative inhibition studies indicate that many tetrahydrocarbazoles also inhibit the mammalian Ca2+-ATPase (SERCA) and Na+,K+-ATPase with an even higher potency than Pma1. We have located the binding site for this compound class by crystallographic structure determination of a SERCA-tetrahydrocarbazole complex to 3.0 Å resolution, finding that the compound binds to a region above the ion inlet channel of the ATPase. A homology model of the Candida albicans H+-ATPase based on this crystal structure, indicates that the compounds could bind to the same pocket and identifies pocket extensions that could be exploited for selectivity enhancement. The results of this study will aid further optimization towards selective H+-ATPase inhibitors as a new class of antifungal agents.
[Mh] Termos MeSH primário: Antifúngicos/farmacologia
Inibidores Enzimáticos/farmacologia
ATPases do Tipo-P/antagonistas & inibidores
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Candida/efeitos dos fármacos
Cristalografia por Raios X
Ensaios de Seleção de Medicamentos Antitumorais
Inibidores Enzimáticos/química
Células Hep G2
Seres Humanos
Potenciais da Membrana/efeitos dos fármacos
Testes de Sensibilidade Microbiana
Modelos Moleculares
Estrutura Molecular
ATPases do Tipo-P/química
Saccharomyces cerevisiae/efeitos dos fármacos
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Carbazoles); 0 (Enzyme Inhibitors); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.3.- (P-type ATPases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180103
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188620

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[Au] Autor:Wiemann P; Perevitsky A; Lim FY; Shadkchan Y; Knox BP; Landero Figueora JA; Choera T; Niu M; Steinberger AJ; Wüthrich M; Idol RA; Klein BS; Dinauer MC; Huttenlocher A; Osherov N; Keller NP
[Ad] Endereço:Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706, USA.
[Ti] Título:Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense.
[So] Source:Cell Rep;19(5):1008-1021, 2017 May 02.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Fenton-chemistry-generating properties of copper ions are considered a potent phagolysosome defense against pathogenic microbes, yet our understanding of underlying host/microbe dynamics remains unclear. We address this issue in invasive aspergillosis and demonstrate that host and fungal responses inextricably connect copper and reactive oxygen intermediate (ROI) mechanisms. Loss of the copper-binding transcription factor AceA yields an Aspergillus fumigatus strain displaying increased sensitivity to copper and ROI in vitro, increased intracellular copper concentrations, decreased survival in challenge with murine alveolar macrophages (AMΦs), and reduced virulence in a non-neutropenic murine model. ΔaceA survival is remediated by dampening of host ROI (chemically or genetically) or enhancement of copper-exporting activity (CrpA) in A. fumigatus. Our study exposes a complex host/microbe multifactorial interplay that highlights the importance of host immune status and reveals key targetable A. fumigatus counter-defenses.
[Mh] Termos MeSH primário: Aspergillus/metabolismo
Interações Hospedeiro-Patógeno
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Células Cultivadas
Proteínas Fúngicas/genética
Proteínas Fúngicas/metabolismo
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos ICR
ATPases do Tipo-P/genética
ATPases do Tipo-P/metabolismo
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Fungal Proteins); 0 (Reactive Oxygen Species); 0 (Transcription Factors); 0 (copper-binding protein); 789U1901C5 (Copper); EC 3.6.3.- (P-type ATPases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE

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