Marcel Faber Roundtable: Is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration?
Marcel Faber Roundtable: Is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration?
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DOI：
10.1007/s10295-005-0077-9
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发表时间：
2006-07-01
影响因子：
3.4
通讯作者：
Baltz, Richard H.
中科院分区：
文献类型：
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作者：
Baltz, Richard H.
今天几乎没有新的抗生素在生产线上。原因可能包括由于筛选的合适化合物来源不足以及验证不佳的发现方法而导致管道前端的饥饿。过去成功的抗生素发现方法，基于放线菌和真菌的天然产物的全细胞抗生素筛选，最终由于已知化合物的重新发现而在管道中间遭受便秘，即使在前端采用低通量方法。目前生产力的缺乏可能是由于对新抗生素发现的战略选择不当。最近应用高通量体外筛选单个抗菌靶标以从组合化学文库、传统化学文库和部分纯化的天然产物提取物中鉴定先导化合物，但尚未产生任何显著的临床候选物。解决目前困境的办法可能是回到天然产品的全细胞筛选。为了使这种方法在本世纪发挥作用，需要将该过程小型化，以使通量比传统筛选提高几个数量级，并且需要通过可以随时监测和改进的方法来最大限度地减少已知抗生素的重新发现。时间。
There are few new antibiotics in the pipeline today. The reasons may include starvation at the front of the pipeline due to inadequate sources of suitable compounds to screen coupled with poorly validated discovery methodologies. A successful antibiotic discovery approach in the past, based upon whole cell antibiotic screening of natural products from actinomycetes and fungi, eventually suffered from constipation in the middle of the pipeline due to rediscovery of known compounds, even though low throughput methodology was employed at the front end. The current lack of productivity may be attributed to the poor choice of strategies to address the discovery of new antibiotics. Recent applications of high throughput in vitro screening of individual antibacterial targets to identify lead compounds from combinatorial chemical libraries, traditional chemical libraries, and partially purified natural product extracts has not produced any significant clinical candidates. The solution to the current dilemma may be to return to natural product whole cell screening. For this approach to work in the current millennium, the process needs to be miniaturized to increase the throughput by orders of magnitude over traditional screening, and the rediscovery of known antibiotics needs to be minimized by methods that can be readily monitored and improved over time.