聚乙二醇-去铁胺：镓缀合物对铜绿假单胞菌外膜渗透性和万古霉素增强作用的影响,Molecular Pharmaceutics

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聚乙二醇-去铁胺：镓缀合物对铜绿假单胞菌外膜渗透性和万古霉素增强作用的影响
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-11-04 , DOI: 10.1021/acs.molpharmaceut.0c00820
Jing Qiao ₁ , Max Purro ₁ , Zhi Liu ₁ , May P Xiong ₁

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由于其外膜的渗透性有限，铜绿假单胞菌表现出广谱的内在抗生素抗性。鉴于这种情况，可以使革兰氏阴性菌更具渗透性并且更容易受到大支架革兰氏阳性抗生素影响的分子可能是有利的。在此，我们评估了一系列靶向聚（乙二醇）-去铁胺/镓 (PEG-DG) 偶联物的抗菌活性，这些偶联物可以提高铜绿假单胞菌对糖肽万古霉素 (VAN)的敏感性。我们观察到以 PEG MW ≥2000 为特征的单端 mPEG-DG 和双端 PEG-DG ₂缀合物协同增强了 VAN 对铜绿假单胞菌的敏感性参考菌株 PAO1 和 ATCC 27853 和三个临床分离的耐碳青霉烯菌株，但不是大肠杆菌菌株 ATCC 25922。虽然目前正在研究这种现象的确切机制，但 PEG-DG 偶联物增强了头孢菌素 (NCF)、碘化己 (HI)和 VAN 通透性仅当 PEG 和 DG 直接结合时。对 VAN 观察到的协同活性有贡献的两个最重要的物理化学因素与 (1) 与聚合物共轭的 DG 配体的最终浓度和 (2) 聚合物长度有关，其中 MW ≥ 2000 产生相似的抑制分数分数。

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Effects of Polyethyelene Glycol-Desferrioxamine:Gallium Conjugates on Pseudomonas aeruginosa Outer Membrane Permeability and Vancomycin Potentiation

Pseudomonas aeruginosa exhibits a broad spectrum of intrinsic antibiotic resistance because of the limited permeability of its outer membrane. Given this situation, molecules that could make Gram-negative bacteria more permeable and more susceptible to large-scaffold Gram-positive antibiotics may be advantageous. Herein, we evaluate the antimicrobial activity of a series of targeted poly(ethylene glycol)-desferrioxamine/gallium (PEG-DG) conjugates that can improve the sensitivity of P. aeruginosa to the glycopeptide vancomycin (VAN). We observed that single-ended mPEG-DG and double-ended PEG-DG₂ conjugates characterized by PEG MW ≥2000 synergistically enhanced the sensitivity of VAN against P. aeruginosa reference strains PAO1 and ATCC 27853 and three clinically isolated carbapenem-resistant strains, but not Escherichia coli strain ATCC 25922. Although the exact mechanism of this phenomenon is currently under investigation, PEG-DG conjugates enhanced nitrocefin (NCF), hexidium iodide (HI), and VAN permeability only when PEG and DG were directly conjugated. The two most important physicochemical factors contributing to the synergistic activity observed with VAN relate to (1) the final concentration of DG ligands conjugated to the polymer and (2) the polymer length, wherein MW ≥2000 yielded a similar fractional inhibitory concentration.

更新日期：2020-11-04

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