Abstract：
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.
摘要：
应用染料了解感染的病因激发了抗菌化学疗法和第一波抗菌药物。第二波抗菌药物的发现是由天然产物的快速发现推动的，现在占目前抗菌药物的69%。但是现在已经发现了最普遍的天然产物，必须筛选107种新的居住在土壤中的细菌物种，以发现一类新的天然产物。因此,而不是第三波抗菌药物的发现，现在有一个发现瓶颈。与数十亿年的微生物拮抗作用所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管理-对小分子如何与细菌生理学相互作用的系统理解，影响所需的表型，并使主机受益。细菌分子遗传学可以阐明与治疗发展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试剂的机制和责任。因此,通过将化学专业知识与细菌感染生物学的系统解剖相结合，可以实现抗菌药物发现的下一阶段。面对雄心勃勃的努力，寻找来自自然界或新自然界的新分子来治愈细菌感染，现代化学生物学和分子遗传学提供的能力可用于寻找新靶标的化学调节剂，以规避普遍的抗性机制。
