Discovery and development of drug cocktails evolved by Nature

自然进化的药物混合物的发现和开发

• 批准号: 10657696
• 负责人: Xuejun Zhu
• 金额: $ 35.08万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657696
• 关键词: Address; Anabolism; Binding; Biological; Collection; Combined Modality Therapy; Development; Drug resistance; Grant; Individual; Metabolic; Methods; Microbe; Natural Products; Natural Selections; Nature; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Population; Process; Production; Recipe; Research; Resistance; System; Therapeutic; combinatorial; design; drug development; drug resistant microorganism; experience; fighting; improved; insight; microbial; microbial genome; multidrug resistance inhibition therapy; natural antimicrobial; process optimization; synergism

PROJECT SUMMARY Discovery and development of new pharmaceuticals and therapeutic alternatives is required to address rapid emergence of drug resistance. An attractive approach is to maximize the potential of currently available drugs through combination therapy. However, de novo design of effective drug cocktails has suffered from the limited understanding of their mechanisms of action or the tedious trial- and-error methods. Moreover, drug resistance can even be aggravated by irrational and abusive usage of noneffective drug cocktails. Therefore, a design strategy for effective cocktail recipe is needed. Numerous observations have suggested that microbes have evolved a large collection of effective drug cocktail recipes to fight against drug resistance after billions of years of natural selection. However, besides a few known examples, co-produced natural products and their combinatorial potential have been overlooked for decades. This is primarily due to the focus of the field on the biological activity of the purified individual compounds, rather than the mixture itself. In addition, it is challenging to predict co- produced natural products based on the genomes of the microbes that synthesize them. Moreover, the synthesis of co-produced and synergistic natural products remains difficult. This MIRA grant will address these challenges. The first research direction is to identify the synergies between intermediates and the final antimicrobial natural products co-produced by single biosynthetic pathways. The structural similarity between these compounds is expected to allow their binding towards the same targets, which can lead to synergistic inhibition of drug-resistant microbes. By characterizing compounds biosynthesized through the same pathways, it is expected to directly provide effective drug cocktail recipe against resistance and to deepen the understanding of the design rules for combination therapy. The second research direction is to address the challenge during the production of the synergistic compounds by dividing their biosynthesis into two bacterial hosts, with one host producing the intermediate, the other producing the final product. It is expected to have three advantages compared to the conventional biosynthesis using a single bacterial host. First, this strategy will reduce the metabolic burden that each bacterial population will experience, and thereby improve the overall production of the final products. Second, the titer ratio of the synergistic intermediates and final products can be fine-tuned by manipulating only one bacterial host, providing modularity during optimization process. Third, the system will produce the compounds with the titer ratio showing the optimal synergistic effect, and then alleviate extensive compound isolation and purification. Overall, the synergy of the two proposed research directions will lead to the discovery of effective drug cocktail recipes against drug resistance, provide fundamental insights for the design rules of combination therapy, and address challenges in the production of these compounds.

项目摘要 需要发现和开发新的药物和治疗替代品， 解决耐药性的迅速出现。一个有吸引力的方法是最大限度地发挥 现有的药物通过联合治疗。然而，有效药物的重新设计 鸡尾酒已经遭受了有限的了解其作用机制或繁琐的审判- 和误差方法此外，不合理和滥用药物甚至会加剧耐药性 无效的药物鸡尾酒。因此，需要有效的鸡尾酒配方的设计策略。 大量的观察表明，微生物已经进化出大量的有效药物， 经过数十亿年的自然选择后，对抗耐药性的鸡尾酒配方。然而，在这方面， 除了一些已知的例子，共同生产的天然产物及其组合潜力， 被忽视了几十年。这主要是由于该领域的重点是生物活性的， 纯化的单个化合物，而不是混合物本身。此外，预测共同- 根据合成它们的微生物的基因组生产天然产物。而且 合成共同产生的和协同的天然产物仍然很困难。这MIRA赠款将解决 这些挑战。第一个研究方向是确定中间体和中间体之间的协同作用 通过单一生物合成途径共同产生的最终抗微生物天然产物。的结构相似性 预期这些化合物之间的相互作用允许它们与相同的靶点结合，这可能导致 协同抑制耐药微生物。通过表征生物合成的化合物， 同样的途径，它有望直接提供有效的药物鸡尾酒配方对抗耐药性， 加深对联合治疗设计规则的理解。第二个研究方向 解决协同化合物生产过程中的挑战， 生物合成到两个细菌宿主中，其中一个宿主产生中间体，另一个产生中间体。 最终产品。与常规生物合成相比，预期其具有三个优点， 单一的细菌宿主首先，这种策略将减少每个细菌群体的代谢负担， 将体验，从而提高最终产品的整体生产。二、滴度比 的协同作用的中间体和最终产品可以微调， 主机，在优化过程中提供模块化。第三，系统会产生化合物， 与效价比显示出最佳的协同效应，然后减轻广泛的化合物分离 和纯化。总的来说，这两个拟议的研究方向的协同作用将导致发现 针对耐药性的有效药物鸡尾酒配方，为设计提供了基本见解 联合治疗的规则，并解决这些化合物的生产中的挑战。