M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, DeGroote School of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8N 4K1, Canada.
Nat Prod Rep. 2017 Jul 1;34(7):694-701. doi: 10.1039/c7np00019g. Epub 2017 Jun 1.
Natural products and their derivatives are mainstays of our antibiotic drugs, but they are increasingly in peril. The combination of widespread multidrug resistance in once susceptible bacterial pathogens, disenchantment with natural products as sources of new drugs, lack of success using synthetic compounds and target-based discovery methods, along with shifting economic and regulatory issues, conspire to move investment in research and development away from the antibiotics arena. The result is a growing crisis in antibiotic drug discovery that threatens modern medicine. 21 century natural product research is perfectly positioned to fill the antibiotic discovery gap and bring new drug candidates to the clinic. Innovations in genomics and techniques to explore new sources of antimicrobial chemical matter are revealing new chemistry. Increasing appreciation of the value of narrow-spectrum drugs and re-examination of once discarded chemical scaffolds coupled with synthetic biology methods to generate new compounds and improve yields offer new strategies to revitalize once moribund natural product programs. The increasing awareness that the combination of antibiotics with adjuvants, non-antibiotic compounds that overcome resistance and enhance drug activity, can rescue older chemical scaffolds, and concepts such as blocking pathogen virulence present orthogonal strategies to traditional antibiotics. In all these areas, natural products offer chemical matter, shaped by natural selection, that is privileged in this therapeutic area. Natural product research is poised to regain prominence in delivering new drugs to solve the antibiotic crisis.
天然产物及其衍生物是我们抗生素药物的主要成分，但它们正日益面临危险。曾经易受细菌病原体感染的细菌对多种药物广泛耐药，对天然产物作为新药来源的失望，使用合成化合物和基于靶点的发现方法缺乏成功，再加上不断变化的经济和监管问题，都促使人们将研发投资从抗生素领域转移出去。其结果是抗生素药物发现的危机日益严重，威胁着现代医学。21 世纪的天然产物研究完全有能力填补抗生素发现的空白，并将新的候选药物推向临床。基因组学的创新和探索新的抗菌化学物质来源的技术正在揭示新的化学物质。人们越来越认识到窄谱药物的价值，重新审视曾经被丢弃的化学支架，并结合合成生物学方法来生成新的化合物并提高产量，为振兴曾经奄奄一息的天然产物项目提供了新的策略。人们越来越意识到，将抗生素与佐剂（克服耐药性并增强药物活性的非抗生素化合物）联合使用，可以挽救旧的化学支架，而阻断病原体毒力等概念则提供了与传统抗生素不同的策略。在所有这些领域，天然产物都提供了经过自然选择塑造的化学物质，在这一治疗领域具有优势。天然产物研究有望重新成为提供新药以解决抗生素危机的焦点。
