The application of dyes to understanding the aetiology of infection inspired antimicrobial chemotherapy and the first wave of antibacterial drugs. The second wave of antibacterial drug discovery was driven by rapid discovery of natural products, now making up 69% of current antibacterial drugs. But now with the most prevalent natural products already discovered, ∼107 new soil-dwelling bacterial species must be screened to discover one new class of natural product. Therefore, instead of a third wave of antibacterial drug discovery, there is now a discovery bottleneck. Unlike natural products which are curated by billions of years of microbial antagonism, the vast synthetic chemical space still requires artificial curation through the therapeutics science of antibacterial drugs — a systematic understanding of how small molecules interact with bacterial physiology, effect desired phenotypes, and benefit the host. Bacterial molecular genetics can elucidate pathogen biology relevant to therapeutics development, but it can also be applied directly to understanding mechanisms and liabilities of new chemical agents with new mechanisms of action. Therefore, the next phase of antibacterial drug discovery could be enabled by integrating chemical expertise with systematic dissection of bacterial infection biology. Facing the ambitious endeavour to find new molecules from nature or new-to-nature which cure bacterial infections, the capabilities furnished by modern chemical biology and molecular genetics can be applied to prospecting for chemical modulators of new targets which circumvent prevalent resistance mechanisms.

中文翻译：

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将细菌分子遗传学与化学生物学相结合，以实现新的抗菌药物发现


应用染料来了解感染的病因激发了抗菌化疗和第一波抗菌药物的出现。第二波抗菌药物发现浪潮是由天然产物的快速发现推动的，目前天然产物占现有抗菌药物的 69%。但现在随着最普遍的天然产物的发现，必须筛选 ∼107 种新的土壤细菌物种才能发现一类新的天然产物。因此，现在抗菌药物发现的瓶颈不是第三波，而是发现瓶颈。与数十亿年微生物拮抗作用产生的天然产物不同，广阔的合成化学空间仍然需要通过抗菌药物的治疗科学进行人工调控——系统地了解小分子如何与细菌生理学相互作用、影响所需的表型并造福于细菌。主持人。细菌分子遗传学可以阐明与治疗开发相关的病原体生物学，但它也可以直接应用于理解具有新作用机制的新化学制剂的机制和责任。因此，下一阶段的抗菌药物发现可以通过将化学专业知识与细菌感染生物学的系统剖析相结合来实现。面对从自然界中寻找治疗细菌感染的新分子的雄心勃勃的努力，现代化学生物学和分子遗传学提供的能力可以应用于寻找规避普遍耐药机制的新靶点的化学调节剂。