Torres Nelson S, Abercrombie Johnathan J, Srinivasan Anand, Lopez-Ribot Jose L, Ramasubramanian Anand K, Leung Kai P
Dental and Craniofacial Trauma Research and Tissue Regeneration, Institute of Surgical Research, JB Fort Sam Houston, Texas, USA Department of Biomedical Engineering, South Texas Center for Emerging Infectious Diseases, The University of Texas, San Antonio, Texas, USA.
Dental and Craniofacial Trauma Research and Tissue Regeneration, Institute of Surgical Research, JB Fort Sam Houston, Texas, USA.
Antimicrob Agents Chemother. 2016 Sep 23;60(10):5663-72. doi: 10.1128/AAC.00377-16. Print 2016 Oct.
It is now well established that bacterial infections are often associated with biofilm phenotypes that demonstrate increased resistance to common antimicrobials. Further, due to the collective attrition of new antibiotic development programs by the pharmaceutical industries, drug repurposing is an attractive alternative. In this work, we screened 1,280 existing commercially available drugs in the Prestwick Chemical Library, some with previously unknown antimicrobial activity, against Staphylococcus aureus, one of the commonly encountered causative pathogens of burn and wound infections. From the primary screen of the entire Prestwick Chemical Library at a fixed concentration of 10 μM, 104 drugs were found to be effective against planktonic S. aureus strains, and not surprisingly, these were mostly antimicrobials and antiseptics. The activity of 18 selected repurposing candidates, that is, drugs that show antimicrobial activity that are not already considered antimicrobials, observed in the primary screen was confirmed in dose-response experiments. Finally, a subset of nine of these drug candidates was tested against preformed biofilms of S. aureus We found that three of these drugs, niclosamide, carmofur, and auranofin, possessed antimicrobial activity against preformed biofilms, making them attractive candidates for repurposing as novel antibiofilm therapies.
现已充分证实，细菌感染通常与生物膜表型相关，这些表型对常见抗菌药物表现出更高的抗性。此外，由于制药行业新抗生素研发项目的集体缩减，药物重新利用是一种有吸引力的替代方法。在这项工作中，我们在Prestwick化学文库中筛选了1280种现有的市售药物，其中一些具有以前未知的抗菌活性，针对金黄色葡萄球菌进行筛选，金黄色葡萄球菌是烧伤和伤口感染中常见的致病病原体之一。在整个Prestwick化学文库以10 μM的固定浓度进行的初步筛选中，发现有104种药物对浮游的金黄色葡萄球菌菌株有效，不出所料，这些药物大多是抗菌剂和防腐剂。在剂量反应实验中证实了在初步筛选中观察到的18种选定的重新利用候选药物的活性，即显示出抗菌活性但尚未被视为抗菌剂的药物。最后，对其中9种候选药物进行了针对金黄色葡萄球菌预先形成的生物膜的测试。我们发现，其中三种药物，氯硝柳胺、卡莫氟和金诺芬，对预先形成的生物膜具有抗菌活性，使其成为作为新型抗生物膜疗法重新利用的有吸引力的候选药物。
