Biotechnology Department, Harvard Extension School, 51 Brattle Street, Cambridge, MA, 02138, United States.
Biotechnology Department, Harvard Extension School, 51 Brattle Street, Cambridge, MA, 02138, United States.
Int J Pharm. 2020 May 15;581:119251. doi: 10.1016/j.ijpharm.2020.119251. Epub 2020 Mar 21.
There is a mounting crisis in treatment of bacterial diseases. The appearance of nosocomial infections produced by multi-drug resistant bacteria is rapidly increasing and at the same time the pharmaceutical industry has been abandoning new antibiotic discovery. To help understand why, we investigated the decision-making processes behind three novel antibiotics that were initially discovered in the late 1980's and early 1990's: daptomycin, linezolid, and lysobactin. Each antibiotic was investigated by two highly qualified scientific organizations that came to opposing opinions regarding the clinical utility and commercial potential of the drug. After reviewing the literature and interviewing key scientific staff members working on each of these molecules, we have identified factors needed to generate positive development decisions. Organizational factors included decision timing, therapeutic area focus, organizational support for risk taking and the presence of a project champion. Technical factors included investment in the optimization of dosing for improved drug exposure, toxicological evaluation of the purified eutomer from a diastereomer and the failure to develop an effective research formulation.
细菌疾病的治疗正面临着日益严重的危机。由多药耐药菌引起的医院感染迅速增多，与此同时，制药行业也一直在放弃新抗生素的发现。为了帮助理解这一点，我们调查了最初在 20 世纪 80 年代末和 90 年代初发现的三种新型抗生素的决策过程：达托霉素、利奈唑胺和 Lysobactin。每个抗生素都由两个非常合格的科学组织进行了调查，这两个组织对药物的临床效用和商业潜力持相反意见。在回顾文献并采访参与这些分子研究的关键科学人员后，我们确定了产生积极开发决策所需的因素。组织因素包括决策时机、治疗领域重点、对冒险的组织支持以及项目冠军的存在。技术因素包括投资于优化剂量以提高药物暴露度、从非对映异构体中纯化药效对映异构体的毒理学评估以及未能开发出有效的研究制剂。
