MICA: Revisiting unexploited natural product antibiotics in the fight against multidrug-resistant bacterial pathogens

20世纪初抗生素在临床上的引入首次使细菌感染的治疗和治愈成为可能，并预示着人类的新纪元。然而，随着致病细菌进化到抵抗它们的影响，这些制剂的有效性已经逐渐被侵蚀，我们现在已经到了细菌感染被证明很难、有时甚至不可能治疗的地步。除非作为紧急事项开发新的抗生素，否则我们面临的无法治疗的细菌感染的规模是自抗生素出现前时代以来未曾见过的，当时死于细菌感染的人在其他健康的人中很常见。事实上，由抗生素耐药细菌引起的感染现在是尚未得到满足的医疗需求中最紧迫的领域之一，世界卫生组织已宣布该问题是目前人类健康面临的三大问题之一。本提案旨在详细调查五种天然产品(微生物产生的化学品)是否有潜力开发为治疗人类细菌感染的新抗生素。近年来，天然产品作为新抗生素的潜在来源一直被忽视，因为相当大一部分抗生素的发现和开发都集中在试图制造新的合成(人造)抗生素上。然而，鉴于天然产品是大多数已在临床使用的抗生素的来源，我们认为它们也可能是新抗生素的最佳来源。为了最大限度地增加我们的天然产品被开发成治疗感染的抗生素药物的可能性，我们选择只追求那些在科学文献中已经有一些证据表明它们对动物的细菌感染有效的药物。这种方法有效地意味着这些天然产品已经克服了许多最重要的障碍，这些障碍阻碍了将化合物开发成安全有效的治疗感染的药物。我们建议从它们产生的微生物中制备五种天然产品抗生素，详细检查它们有效抑制细菌生长/杀死细菌的能力，并确定它们是如何做到这一点的，并在细菌感染模型中确认它们是安全有效的。这些研究的结果将提供重要的基础科学知识，并将确定这些天然产物中的一种或多种是否适合进一步开发为抗生素药物。该项目将与天然产品抗生素的行业领先者Cubist PharmPharmticals合作进行；通过利用学术界和工业界在抗生素研究方面的互补优势和能力，我们的目标是建立一个能够将这些新型抗生素从工作台发展到床边的协同合作伙伴关系。

The clinical introduction of antibiotics in the early years of the 20th century enabled for the first time the treatment and cure of bacterial infections, and heralded a new era for humanity. However, the usefulness of these agents has become steadily eroded as disease-causing bacteria have evolved to resist their effects, and we have now reached a point where bacterial infections can prove difficult, sometimes even impossible, to treat. Unless new antibiotics are developed as a matter of urgency, we face untreatable bacterial infections on a scale not seen since the pre-antibiotic era, a time when death from bacterial infection in otherwise-healthy individuals was common. Indeed, infections caused by antibiotic-resistant bacteria now represent one of the most pressing areas of unmet medical need, and the World Health Organization has declared the problem one of the top three currently facing human health. The present proposal aims to investigate in detail five natural products (chemicals produced by microorganisms) for their potential to be developed into new antibiotics for treating bacterial infections in humans. Natural products have been rather overlooked in recent years as a potential source of new antibiotics, since a considerable proportion of antibiotic discovery and development has focused on trying to make new synthetic (man-made) antibiotics. However, in view of the fact that natural products are the source of the majority of antibiotics already in clinical use, we believe that they likely also represent the best source of new antibiotics. To maximize the likelihood that our natural products can be developed into antibiotic drugs for treating infection, we have chosen to pursue only those for which there is already some evidence in the scientific literature that they are effective against bacterial infection in animals. This approach effectively means that these natural products have already overcome many of the most significant hurdles that stand in the way of developing chemical compounds into safe and effective drugs to treat infection.We propose to prepare the five natural product antibiotics from their producing microorganisms, examine in detail their ability to effectively inhibit the growth/kill bacteria and establish how they do this, and confirm that they are safe and effective in models of bacterial infection. The results of these studies will provide important fundamental scientific knowledge, and will establish whether one or more of these natural products are suitable for further development into antibiotic drugs. The project will be conducted in collaboration with Cubist Pharmaceuticals, an industry-leader in natural product antibiotics; by harnessing complementary strengths and capabilities in antibiotic research within academia and industry, we aim to establish a synergistic partnership capable of progressing these novel antibiotics from bench to bedside.