Repurposing Screen Identifies Unconventional Drugs With Activity Against Multidrug Resistant Acinetobacter baumannii
Repurposing Screen Identifies Unconventional Drugs With Activity Against Multidrug Resistant Acinetobacter baumannii
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DOI：
10.3389/fcimb.2018.00438
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发表时间：
2019-01-04
影响因子：
5.7
通讯作者：
Zheng, Wei
中科院分区：
文献类型：
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作者：
Cheng, Yu-Shan;Sun, Wei;Zheng, Wei
耐药医院感染是一个新兴的公共卫生问题：耐碳青霉烯类革兰氏阴性细菌，如鲍曼不动杆菌，是迫切需要新的治疗药物的病原体之一。最近，药物再利用已成为快速确定有效药物和药物组合以对抗耐药细菌的另一种方法。我们对高毒力、多药耐药的鲍曼不动杆菌AB5075菌株进行了药物再利用筛选。这种从患者身上分离出来的菌株对25种革兰氏阴性细菌的一线抗生素具有抗药性。使用细菌生长试验的化合物筛选导致了43个活性化合物的鉴定和确认。在这些确认的化合物中，有7个是非抗菌适应症的批准药物或药理活性化合物。其中三种药物，5-氟尿嘧啶、氟比林和BAY 11-7082以两种药物组合的形式对阿奇霉素和粘菌素复敏菌株AB5075。这种方法使用从患者分离的病原体样本的药物再用途筛选和高通量细菌生长试验，成功地识别了克服多重耐药细菌感染的新药组合。
Antibiotic-resistant nosocomial infections are an emerging public health issue: carbapenem-resistant gram-negative bacteria such as Acinetobacter baumannii are among the pathogens against which new therapeutic agents are desperately needed. Drug repurposing has recently emerged as an alternative approach to rapidly identifying effective drugs and drug combinations to combat drug resistant bacteria. We performed a drug repurposing screen against a highly virulent, multidrug resistant, Acinetobacter baumannii strain AB5075. This strain, isolated from a patient, is resistant to 25 first-line antibiotics for gram-negative bacteria. A compound screen using a bacterial growth assay led to identification and confirmation of 43 active compounds. Among these confirmed compounds, seven are approved drugs or pharmacologically active compounds for non-antimicrobial indications. Three of these drugs, 5-fluorouracil, fluspirilene, and Bay 11-7082 resensitized strain AB5075 to azithromycin and colistin in a two-drug combination format. The approach using a drug repurposing screen with a pathogen sample isolated from a patient and a high throughput bacterial growth assay led to the successful identification of new drug combinations to overcome a multidrug resistant bacterial infection.