Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
Chemical Biology Ventures Ltd, 123 Alexander Close, Abingdon, Oxfordshire OX14 1XD, UK.
J Antimicrob Chemother. 2018 Jun 1;73(6):1452-1459. doi: 10.1093/jac/dky019.
Antibiotic (antibacterial) resistance is a serious global problem and the need for new treatments is urgent. The current antibiotic discovery model is not delivering new agents at a rate that is sufficient to combat present levels of antibiotic resistance. This has led to fears of the arrival of a 'post-antibiotic era'. Scientific difficulties, an unfavourable regulatory climate, multiple company mergers and the low financial returns associated with antibiotic drug development have led to the withdrawal of many pharmaceutical companies from the field. The regulatory climate has now begun to improve, but major scientific hurdles still impede the discovery and development of novel antibacterial agents. To facilitate discovery activities there must be increased understanding of the scientific problems experienced by pharmaceutical companies. This must be coupled with addressing the current antibiotic resistance crisis so that compounds and ultimately drugs are delivered to treat the most urgent clinical challenges. By understanding the causes of the failures and successes of the pharmaceutical industry's research history, duplication of discovery programmes will be reduced, increasing the productivity of the antibiotic drug discovery pipeline by academia and small companies. The most important scientific issues to address are getting molecules into the Gram-negative bacterial cell and avoiding their efflux. Hence screening programmes should focus their efforts on whole bacterial cells rather than cell-free systems. Despite falling out of favour with pharmaceutical companies, natural product research still holds promise for providing new molecules as a basis for discovery.
抗生素（抗菌）耐药性是一个严重的全球问题，急需新的治疗方法。目前的抗生素发现模式无法以足够快的速度产生新的药物来对抗目前的抗生素耐药水平。这导致人们担心会进入“后抗生素时代”。科学上的困难、不利的监管环境、多家公司的合并以及与抗生素药物开发相关的低财务回报，导致许多制药公司退出了这一领域。监管环境现在已经开始改善，但重大的科学障碍仍然阻碍了新型抗菌药物的发现和开发。为了促进发现活动，必须增加对制药公司所面临的科学问题的了解。这必须与解决当前的抗生素耐药性危机相结合，以便将化合物并最终将药物用于治疗最紧迫的临床挑战。通过了解制药业研究历史的失败和成功的原因，可以减少发现计划的重复，从而提高学术界和小公司的抗生素药物发现管道的生产力。需要解决的最重要的科学问题是将分子送入革兰氏阴性细菌细胞并避免它们外排。因此，筛选计划应将其努力集中在整个细菌细胞上，而不是无细胞系统上。尽管不受制药公司青睐，但天然产物研究仍然有希望提供新的分子作为发现的基础。
