STTR Phase I: New Synergistic Biofungicides - Novel Aminoglycoside and Azole/Strobulin Combinations

这个小企业技术（STTR）项目的更广泛的影响/商业潜力是开发新的和变革性的杀真菌策略，这些策略更有效，更环保，毒性更低，但仍然以合理和有竞争力的成本生产和提供。超过80%的作物和草坪疾病是由于真菌感染。直接施用化学杀真菌剂仍然是控制这些疾病的最有效和最广泛使用的策略。作物杀真菌剂市场的很大一部分包括两类杀真菌剂：三唑类和strobulins。这两类药物的使用量越来越大，以克服正在形成的耐药性，并且在高水平使用时都具有已知的人类和动物毒性。对用于治疗急性人类和动物真菌病（例如曲霉病）的治疗性抗真菌剂的新出现的抗性与最广泛使用的三唑类作物杀真菌剂的过度使用直接相关。因此，由于抗性、环境影响、动物/人类毒性和成本而导致的效力下降对这些和其他化学杀真菌剂的使用提出了挑战。本提案中所述的与三唑类和嗜球果伞素协同作用的新型抗真菌氨基糖苷类K20的研究和使用解决了这些挑战，以及对这种变革策略的需求。本STTR I期项目提出开发高产率和纯度的氨基糖苷类杀真菌剂K20的合成方案，并使用标准棋盘分析确定每批K20与叶菌唑或吡唑醚菌酯的组合的部分抑制浓度指数（FICI）。 此外，计划进行K20-杀菌剂组合对小麦赤霉病（FHB）的温室和田间试验。在显示协同作用的组合中，K20与叶菌唑和吡唑醚菌酯混合。这些杀真菌剂的广泛和大量使用与许多环境和人类/动物健康问题有关。对作物病原体禾谷镰刀菌（小麦、大麦和玉米的镰刀菌头枯病（FHB）的病原体）观察到显著且一致的协同抑制活性。K20与这些常用杀菌剂之间的增效作用具有广泛而重要的意义。它提供了使用大幅减少的杀真菌剂来保护作物的可能性，这将抵消全球真菌耐药性的增加，并扭转人类和动物健康问题的上升。

The broader impact/commercial potential of this Small Business Technology (STTR) project is the development of new and transformative fungicidal strategies that are more effective, ecofriendly, less toxic, but still produced and available at reasonable and competitive cost. More than 80% of crop and turf diseases are due to fungal infections. Direct application of chemical fungicides continues to be the most effective and widely used strategy to control these diseases. A large fraction of the crop fungicide market includes two fungicide classes: The triazoles and strobulins. Both classes are used in increasingly larger amounts to overcome developing resistance, and both have known human and animal toxicities when used at high levels. Emerging resistance to therapeutic antifungals for treatment of acute human and animal fungal diseases (e.g. aspergillosis) has been directly linked to the overuse of the most widely used triazole crop fungicides. Therefore, declining effectiveness due to resistance, environmental impacts, animal/human toxicity, and costs challenge the use of these and other chemical fungicides. The research and use of the novel antifungal aminoglycoside K20 that acts synergistically with triazoles and strobulins as described in this proposal address these challenges, and the need for such transformative strategies.This STTR Phase I project proposes to develop the synthetic protocol for production of aminoglycoside fungicide K20 in high yield and purity, and determine the fractional inhibitory concentration index (FICI) for each batch of K20 in combination with metconazole or pyrachlostrobin using standard checkerboard analyses. In addition, the plan is to conduct greenhouse and field tests of K20-fungicide combinations against Fusarium head blight (FHB) disease of wheat. Among the combinations showing synergy are K20 mixed with metconazole and pyrachlostrobin. The widespread and heavy use of these fungicides has been linked to a number of environmental and human/animal health issues. Striking and consistent synergistic inhibitory activities are observed with the crop pathogen Fusarium graminearum - the causative agent of Fusarium head blight (FHB) of wheat, barley and corn. The synergism between K20 and these widely used fungicides has broad and important implications. It offers the possibility of using dramatically smaller amounts of fungicides for crop protection, which will counter the increases in global fungal resistance, and reverse the rise in human and animal health problems.