一种截短侧耳素衍生物与强力霉素的新组合用于治疗多重耐药鲍曼不动杆菌
A New Combination of a Pleuromutilin Derivative and Doxycycline for Treatment of Multidrug-Resistant Acinetobacter baumannii.
作者信息
Siricilla Shajila, Mitachi Katsuhiko, Yang Junshu, Eslamimehr Shakiba, Lemieux Maddie R, Meibohm Bernd, Ji Yinduo, Kurosu Michio
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
Department of Veterinary and Biomedical Sciences, University of Minnesota , 205 VSB, 1971 Commonwealth Avenue, St. Paul, Minnesota 55108, United States.
出版信息
J Med Chem. 2017 Apr 13;60(7):2869-2878. doi: 10.1021/acs.jmedchem.6b01805. Epub 2017 Mar 22.
Abstract
Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most difficult Gram-negative bacteria to treat and eradicate. In a cell-based screening of pleuromutilin derivatives against a drug sensitive A. baumannii strain, new molecules (2-4) exhibit bacteriostatic activity with 3.13 μg/mL concentration and 1 shows bactericidal activity with an MBC of 6.25 μg/mL. The pleuromutilin derivative 1 displays strong synergistic effects with doxycycline in a wide range of concentrations. A 35/1 ratio of 1 and doxycycline (1-Dox 35/1) kills drug susceptible A. baumannii with the MBC of 2.0 μg/mL and an MDR A. baumannii with the MBC of 3.13 μg/mL. In vitro anti-Acinetobacter activity of 1-Dox 35/1 is superior to that of clinical drugs such as tobramycin, tigecycline, and colistin. The efficacy of 1-Dox 35/1 is evaluated in a mouse septicemia model; treatment of the infected C57BL/6 mice with 1-Dox 35/1 protects from lethal infection of A. baumannii with an ED value of <2.0 mg/kg.
摘要
多重耐药鲍曼不动杆菌是最难治疗和根除的革兰氏阴性菌之一。在针对一株药敏鲍曼不动杆菌的基于细胞的截短侧耳素衍生物筛选中，新分子（2 - 4）在浓度为3.13 μg/mL时表现出抑菌活性，而分子1在最低杀菌浓度（MBC）为6.25 μg/mL时表现出杀菌活性。截短侧耳素衍生物1在广泛的浓度范围内与强力霉素表现出强烈的协同作用。1与强力霉素的比例为35/1（1 - Dox 35/1）时，能杀死药敏鲍曼不动杆菌，其MBC为2.0 μg/mL，也能杀死多重耐药鲍曼不动杆菌，其MBC为3.13 μg/mL。1 - Dox 35/1的体外抗不动杆菌活性优于妥布霉素、替加环素和黏菌素等临床药物。在小鼠败血症模型中评估了1 - Dox 35/1的疗效；用1 - Dox 35/1治疗感染的C57BL/6小鼠可使其免受鲍曼不动杆菌的致命感染，其半数有效剂量（ED）值<2.0 mg/kg。
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