RESUMO
Brettanomyces (Dekkera) bruxellensis is an ascomycetous yeast of major importance in the food, beverage and biofuel industry. It has been isolated from various man-made ecological niches that are typically characterized by harsh environmental conditions such as wine, beer, soft drink, etc. Recent comparative genomics studies revealed an immense intraspecific diversity, but it is still unclear whether this genetic diversity also leads to systematic differences in fermentation performance and (off-)flavor production, and to what extent strains have evolved to match their ecological niche. Here, we present an evaluation of the fermentation properties of eight genetically diverse B. bruxellensis strains originating from beer, wine and soft drinks. We show that sugar consumption and aroma production during fermentation are determined by both the yeast strain and composition of the medium. Furthermore, our results indicate a strong niche adaptation of B. bruxellensis, most clearly for wine strains. For example, only strains originally isolated from wine were able to thrive well and produce the typical Brettanomyces-related phenolic off-flavors 4-ethylguaiacol and 4-ethylphenol when inoculated in red wine. Sulfite tolerance was found as a key factor explaining the observed differences in fermentation performance and off-flavor production. Sequence analysis of genes related to phenolic off-flavor production, however, revealed only marginal differences between the isolates tested, especially at the amino acid level. Altogether, our study provides novel insights in the Brettanomyces metabolism of flavor production, and is highly relevant for both the wine and beer industry.
Assuntos
Brettanomyces/metabolismo , Metabolismo dos Carboidratos , Fermentação , Microbiologia de Alimentos , Compostos Orgânicos Voláteis/metabolismo , Adaptação Biológica , Brettanomyces/classificação , Brettanomyces/genética , Brettanomyces/isolamento & purificação , Meios de Cultura/química , Variação GenéticaRESUMO
To meet their carbohydrate requirements, adult parasitoids exploit a broad range of sugar resources, including floral and extrafloral nectar and honeydew. Although honeydew might be the predominant sugar source, especially in agricultural systems, it often is nutritionally inferior to sugar sources like nectar. Given its broad availability, it may be expected that sugar-feeding insects have evolved specialized adaptations to deal with this typically inferior sugar source. This would apply especially to organisms that have a close association with honeydew producers. Here, we hypothesized that parasitoids of honeydew-producing insects should show a pronounced response to sugars, such as fructose, sucrose, melezitose, and trehalose, and to a lesser extent glucose. To test this hypothesis, we investigated sugar consumption, feeding behavior and survival of the aphid parasitoid Aphidius ervi on several sugars (equiweight solutions). Our results show that A. ervi adults consumed typical honeydew sugars (sucrose, fructose, trehalose, and melezitose) the most, while consuming considerably less glucose or melibiose. Rhamnose, which does not occur in aphid honeydew, was not, or was only marginally, consumed. When different sugars were provided at the same time, A. ervi adults preferred sucrose or fructose over glucose or melezitose. Furthermore, pre-exposure to sucrose or fructose significantly reduced subsequent intake of glucose, suggesting an acquired distaste for glucose after being previously exposed to highly preferred sugars such as sucrose and fructose. Altogether, this study shows that A. ervi adults prefer sugars (fructose, melezitose, trehalose, and sucrose) that are overrepresented in aphid honeydew and show a lower preference to one (glucose) that is underrepresented in honeydew.
Assuntos
Afídeos/parasitologia , Metabolismo dos Carboidratos , Vespas/fisiologia , Animais , Afídeos/fisiologia , Carboidratos/análise , Metabolismo Energético , Comportamento Alimentar , Feminino , Longevidade , MasculinoRESUMO
Invasive aspergillosis (IA) has become increasingly common and is characterised by high morbidity and mortality. Upcoming resistance threatens treatment with azoles and highlights the continuous need for novel therapeutics. This laboratory study investigated the in vitro and in vivo potential of the alkylphospholipid oleylphosphocholine (OlPC) against Aspergillus. In vitro activities of OlPC, miltefosine, posaconazole and voriconazole were determined for Aspergillus fumigatus, A. niger, A. terreus and A. flavus. In vivo efficacy of OlPC was evaluated in a systemic A. fumigatus mouse model, adopting a short-term and long-term oral or intraperitoneal dosing regimen. OlPC showed good in vitro activity against A. fumigatus (IC50 = 1.04 µmol l(-1)). Intraperitoneal administration of 50 mg kg(-1) day(-1) OlPC significantly reduced the fungal organ burdens at 4 days post-infection (dpi). Although 5- and 10-day OlPC treatment improved survival, organ burdens were not affected at 10 and 15 dpi. While this study showed excellent in vitro activity of OlPC against Aspergillus spp., its therapeutic efficacy in an acute mouse model for IA was less convincing. Given the limited therapeutic options in the current antifungal market for invasive infections, OlPC activity should be assessed in a less stringent in vivo model, potentially in combination treatment with other already marketed antifungal drugs.
Assuntos
Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergillus/efeitos dos fármacos , Fosforilcolina , Pirimidinas/uso terapêutico , Animais , Aspergilose/microbiologia , Aspergillus fumigatus/efeitos dos fármacos , Azóis/uso terapêutico , Modelos Animais de Doenças , Camundongos , Testes de Sensibilidade Microbiana , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Fosforilcolina/uso terapêutico , Triazóis/farmacologia , Voriconazol/farmacologiaRESUMO
BACKGROUND: Pyrrolo[1,2-α][1,4]benzodiazepines (PBDs) have been described as a novel class of antifungal compounds with activity against dermatophytes and Aspergillus fumigatus. The initial structure-activity relationship showed that compounds with a chlorine substitution at position 7 have a higher activity compared with regioisomers or other substituents. METHODS: The present study evaluated more analogues with a 7-chlorine-substitution in vitro against a broad panel of clinically relevant fungal species. The Microsporum canis model in guinea pigs was used to assess the in vivo efficacy after oral and topical administration. RESULTS: IC50 values in the low micromolar range (IC50 0.6-8.0 µM for dihydro-PBDs; 0.1-0.7 µM for oxidized PBDs) confirmed the potent and selective in vitro activity of PBDs against dermatophytes, while the activity against A. fumigatus and Candida parapsilosis was slightly lower. For dihydro-PBDs, para-substitution showed superior activity, while oxidized compounds with a meta-substitution performed best. Oxidized Compound O with meta-CF2CH3-substitution showed excellent IC50 values of 0.6 µM against M. canis, 2.0 µM against Trichophyton mentagrophytes and 0.7 µM against Trichophyton rubrum, matching or outperforming the activity of itraconazole (IC50 values of 2.0, 0.4 and 0.6 µM, respectively). In vivo, topical application of a 0.25% formulation of Compound O gave a lesion reduction of >90% compared with placebo-treated animals. Oral administration of this compound at 20 mg/kg showed superior therapeutic efficacy compared with the reference drug itraconazole. CONCLUSIONS: In conclusion, PBDs with a chlorine atom at position 7 are very promising antifungal candidates with convincing in vitro and in vivo activity particularly against dermatophytes and should be studied in greater detail to explore their full potential in the treatment of dermatophytoses.
Assuntos
Antifúngicos/farmacologia , Azepinas/farmacologia , Dermatomicoses/microbiologia , Microsporum/efeitos dos fármacos , Pirróis/farmacologia , Administração Oral , Administração Tópica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Azepinas/administração & dosagem , Azepinas/farmacocinética , Linhagem Celular , Dermatomicoses/tratamento farmacológico , Modelos Animais de Doenças , Cobaias , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Pirróis/administração & dosagem , Pirróis/farmacocinéticaRESUMO
The triazole antifungal pramiconazole (Stiefel, a GSK company) was compared with itraconazole, miconazole, and terbinafine in vitro and in vivo. Potent in vitro activities against Candida spp. (50% inhibitory concentration [IC50], 0.04 to 1.83 µM) and Microsporum and Trichophyton spp. (IC50, 0.15 to 1.34 µM) were obtained but not, however, against other filamentous molds and zygomycetes. In the M. canis guinea pig model and C. albicans vulvovaginitis rat model, pramiconazole was superior to the reference compounds after oral and topical administration.
Assuntos
Candida albicans/patogenicidade , Dermatite/microbiologia , Imidazóis/uso terapêutico , Microsporum/patogenicidade , Triazóis/uso terapêutico , Vaginite/microbiologia , Administração Tópica , Animais , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Feminino , Cobaias , Humanos , Imidazóis/farmacocinética , Concentração Inibidora 50 , Itraconazol/farmacocinética , Itraconazol/uso terapêutico , Naftalenos/farmacocinética , Naftalenos/uso terapêutico , Terbinafina , Triazóis/farmacocinéticaRESUMO
Fungi of the genus Aspergillus are widespread in the environment. Some Aspergillus species, most commonly Aspergillus fumigatus, may lead to a variety of allergic reactions and life-threatening systemic infections in humans. Invasive aspergillosis occurs primarily in patients with severe immunodeficiency, and has dramatically increased in recent years. There are several factors at play that contribute to aspergillosis, including both fungus and host-related factors such as strain virulence and host pulmonary structure/immune status, respectively. The environmental tenacity of Aspergilllus, its dominance in diverse microbial communities/habitats, and its ability to navigate the ecophysiological and biophysical challenges of host infection are attributable, in large part, to a robust stress-tolerance biology and exceptional capacity to generate cell-available energy. Aspects of its stress metabolism, ecology, interactions with diverse animal hosts, clinical presentations and treatment regimens have been well-studied over the past years. Here, we synthesize these findings in relation to the way in which some Aspergillus species have become successful opportunistic pathogens of human- and other animal hosts. We focus on the biophysical capabilities of Aspergillus pathogens, key aspects of their ecophysiology and the flexibility to undergo a sexual cycle or form cryptic species. Additionally, recent advances in diagnosis of the disease are discussed as well as implications in relation to questions that have yet to be resolved.
Assuntos
Aspergilose/microbiologia , Aspergilose/patologia , Aspergillus/fisiologia , Aspergillus/patogenicidade , Fenômenos Biofísicos , Interações Hospedeiro-Patógeno , Animais , Aspergilose/diagnóstico , Testes Diagnósticos de Rotina , Ecossistema , HumanosRESUMO
Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ-42756493 in patients with tumors harboring FGFR pathway alterations. Mol Cancer Ther; 16(6); 1010-20. ©2017 AACR.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Quinoxalinas/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Lisossomos/metabolismo , Masculino , Camundongos , Terapia de Alvo Molecular , Fosforilação , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Quinoxalinas/administração & dosagem , Quinoxalinas/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Although Aspergillus infections pose a growing threat to immunocompromised individuals, the limited range of existing drugs does not allow efficient management of invasive aspergillosis. Moreover, drug resistance is becoming increasingly common. Given that drug discovery relies on high-quality animal studies, careful design of in vivo models for invasive aspergillosis could facilitate the identification of novel antifungals. In this review, we discuss key aspects of animal models for invasive aspergillosis, covering laboratory animal species, immune modulation, inoculation routes, Aspergillus strains, treatment strategies and efficacy assessment, to enable the reader to tailor specific protocols for different types of preclinical antifungal evaluation study.