Chemigenetic analysis and efficacy of novel antifungal drugs that target fungal pH signalling

针对真菌 pH 信号传导的新型抗真菌药物的化学遗传学分析和功效

• 批准号: BB/V017004/1
• 负责人: Elaine Bignell
• 金额: $ 67.9万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV017004%2F1
• 关键词: Chemigenetic; analysis; efficacy; novel; antifungal

Collectively, fungal diseases pose a greater threat to animals, plants and ecosystems than other types of infectious micro-organism. Fungal infections of man kill millions and most often occur in patients with severe underlying health conditions such as cancer, or chronic lung disorders such as cystic fibrosis. Fungal infections of plants destroy enough crops annually to feed many millions of people. However, there are a very limited number of antifungal drugs available for use agriculturally or in the clinic and some classes of antifungal drugs, for example the azoles. are therefore used to treat both human and plant fungal infections. In 2018 azole-based fungicides accounted for 34% of the antifungal agents used to treat crops. Worryingly, resistance to all classes of available antifungal drugs is increasing and azole resistance occurring in agricultural settings crosses over into the clinic in around 40% of cases in some settings. This project builds on decades of previous genetic and infection studies, including a PhD project where a new set of chemicals were showed as having antifungal activity. These chemicals attack a fungal signalling mechanism needed for infection and invasion by fungal pathogens in man, plants, animals and we will now work to understand how they work. We will also try to make them more potent, and work with industry to develop them for use in agriculture or in the clinic.

总的来说，真菌疾病对动物、植物和生态系统的威胁比其他类型的传染性微生物更大。人类真菌感染导致数百万人死亡，最常发生在患有严重潜在健康状况（如癌症）或慢性肺部疾病（如囊性纤维化）的患者中。植物的真菌感染每年摧毁足够养活数百万人的农作物。然而，可用于农业或临床的抗真菌药物的数量非常有限，并且某些类别的抗真菌药物，例如唑类。因此用于治疗人类和植物真菌感染。2018年，唑类杀菌剂占用于处理作物的抗真菌剂的34%。令人担忧的是，对所有类别的可用抗真菌药物的耐药性正在增加，在某些情况下，农业环境中发生的唑类耐药性在约40%的病例中交叉进入临床。该项目建立在几十年前的遗传和感染研究的基础上，包括一个博士项目，其中一组新的化学物质被证明具有抗真菌活性。这些化学物质攻击真菌信号机制，这些机制是真菌病原体感染和入侵人类、植物和动物所必需的，我们现在将努力了解它们是如何工作的。我们还将努力使它们更有效，并与工业界合作开发它们用于农业或临床。

项目成果

Tackling the emerging threat of antifungal resistance to human health.

• DOI: 10.1038/s41579-022-00720-1
• 发表时间: 2022-09
• 期刊: Nature reviews. Microbiology
• 作者: Fisher MC;Alastruey-Izquierdo A;Berman J;Bicanic T;Bignell EM;Bowyer P;Bromley M;Brüggemann R;Garber G;Cornely OA;Gurr SJ;Harrison TS;Kuijper E;Rhodes J;Sheppard DC;Warris A;White PL;Xu J;Zwaan B;Verweij PE
• 通讯作者: Verweij PE

Heightened efficacy of anidulafungin when used in combination with manogepix or 5-flucytosine against Candida auris in vitro

阿尼芬净与 manogepix 或 5-氟胞嘧啶联合使用可提高体外抗念珠菌的功效

• DOI: 10.1101/2022.12.16.520848
• 发表时间: 2022
• 作者: John L

Distinct Cohorts of Aspergillus fumigatus Transcription Factors Are Required for Epithelial Damage Occurring via Contact- or Soluble Effector-Mediated Mechanisms.

• DOI: 10.3389/fcimb.2022.907519
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7

Developing novel antifungals: lessons from G protein-coupled receptors.

• DOI: 10.1016/j.tips.2022.12.002
• 发表时间: 2023-03
• 期刊: Trends in pharmacological sciences
• 影响因子: 13.8
• 作者: Velazhahan V;McCann BL;Bignell E;Tate CG
• 通讯作者: Tate CG

Aspergillus fumigatus drives tissue damage via iterative assaults upon mucosal integrity and immune homeostasis

烟曲霉通过对粘膜完整性和免疫稳态的反复攻击来驱动组织损伤

• DOI: 10.1101/2021.11.09.468003
• 发表时间: 2021
• 作者: Okaa U