Gilbert-Girard Shella, Savijoki Kirsi, Yli-Kauhaluoma Jari, Fallarero Adyary
Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
Microorganisms. 2020 Nov 21;8(11):1834. doi: 10.3390/microorganisms8111834.
In an effort to find new repurposed antibacterial compounds, we performed the screening of an FDA-approved compounds library against American Type Culture Collection (ATCC) 25923. Compounds were evaluated for their capacity to prevent both planktonic growth and biofilm formation as well as to disrupt pre-formed biofilms. One of the identified initial hits was fingolimod (FTY720), an immunomodulator approved for the treatment of multiple sclerosis, which was then selected for follow-up studies. Fingolimod displayed a potent activity against and with a minimum inhibitory concentration (MIC) within the range of 12-15 µM at which concentration killing of all the bacteria was confirmed. A time-kill kinetic study revealed that fingolimod started to drastically reduce the viable bacterial count within two hours and we showed that no resistance developed against this compound for up to 20 days. Fingolimod also displayed a high activity against (MIC 25 µM) as well as a modest activity against and . In addition, fingolimod inhibited quorum sensing in and might therefore target this signaling pathway in certain Gram-negative bacteria. In conclusion, we present the identification of fingolimod from a compound library and its evaluation as a potential repurposed antibacterial compound.
为了寻找新的抗菌化合物，我们对一个经美国食品药品监督管理局（FDA）批准的化合物文库进行了筛选，测试其对美国典型培养物保藏中心（ATCC）25923菌株的抗菌活性。评估了这些化合物预防浮游菌生长和生物膜形成以及破坏已形成生物膜的能力。最初筛选出的活性化合物之一是芬戈莫德（FTY720），一种已被批准用于治疗多发性硬化症的免疫调节剂，随后被选作后续研究对象。芬戈莫德对[具体细菌名称1]和[具体细菌名称2]显示出强大的活性，其最低抑菌浓度（MIC）在12 - 15 μM范围内，在此浓度下可确认能杀死所有细菌。时间 - 杀菌动力学研究表明，芬戈莫德在两小时内开始大幅降低活菌数量，并且我们发现长达20天内该化合物都未产生耐药性。芬戈莫德对[具体细菌名称3]也显示出高活性（MIC 25 μM），对[具体细菌名称4]和[具体细菌名称5]也有一定活性。此外，芬戈莫德抑制了[具体细菌名称6]中的群体感应，因此可能在某些革兰氏阴性细菌中靶向该信号通路。总之，我们展示了从化合物文库中鉴定出芬戈莫德，并将其评估为一种潜在的抗菌化合物。
