Department of Dermatology, Emory University School of Medicine, Atlanta, GA, USA.
Molecular and Systems Pharmacology Program, Emory University, Atlanta, GA, USA.
Sci Rep. 2020 Sep 18;10(1):15340. doi: 10.1038/s41598-020-72331-w.
The rise of antibiotic resistance has necessitated a search for new antimicrobials with potent activity against multidrug-resistant gram-negative pathogens, such as carbapenem-resistant Acinetobacter baumannii (CRAB). In this study, a library of botanical extracts generated from plants used to treat infections in traditional medicine was screened for growth inhibition of CRAB. A crude extract of Schinus terebinthifolia leaves exhibited 80% inhibition at 256 µg/mL and underwent bioassay-guided fractionation, leading to the isolation of pentagalloyl glucose (PGG), a bioactive gallotannin. PGG inhibited growth of both CRAB and susceptible A. baumannii (MIC 64-256 µg/mL), and also exhibited activity against Pseudomonas aeruginosa (MIC 16 µg/mL) and Staphylococcus aureus (MIC 64 µg/mL). A mammalian cytotoxicity assay with human keratinocytes (HaCaTs) yielded an IC for PGG of 256 µg/mL. Mechanistic experiments revealed iron chelation as a possible mode of action for PGG's activity against CRAB. Passaging assays for resistance did not produce any resistant mutants over a period of 21 days. In conclusion, PGG exhibits antimicrobial activity against CRAB, but due to known pharmacological restrictions in delivery, translation as a therapeutic may be limited to topical applications such as wound rinses and dressings.
抗生素耐药性的上升使得人们迫切需要寻找新的抗菌药物，这些药物对多重耐药革兰氏阴性病原体（如耐碳青霉烯鲍曼不动杆菌[CRAB]）具有强大的活性。在这项研究中，从用于治疗传统医学感染的植物中生成的植物提取物文库被筛选以抑制 CRAB 的生长。印防己毒素叶的粗提取物在 256μg/mL 时表现出 80%的抑制作用，并进行了基于生物测定的分离，导致分离出具有生物活性的五没食子酰葡萄糖（PGG）。PGG 抑制 CRAB 和敏感的鲍曼不动杆菌的生长（MIC64-256μg/mL），并且还对铜绿假单胞菌（MIC16μg/mL）和金黄色葡萄球菌（MIC64μg/mL）表现出活性。用人角质形成细胞（HaCaTs）进行的哺乳动物细胞毒性测定显示 PGG 的 IC50 为 256μg/mL。机制实验表明铁螯合可能是 PGG 抑制 CRAB 活性的作用模式之一。在 21 天的时间内，进行耐药性传代实验没有产生任何耐药突变体。总之，PGG 对 CRAB 表现出抗菌活性，但由于已知在药物输送方面的药理学限制，作为治疗药物的转化可能仅限于局部应用，如伤口冲洗和敷料。
