Activity and Interactions of Liposomal Antibiotics in Presence of Polyanions and Sputum of Patients with Cystic Fibrosis
Activity and Interactions of Liposomal Antibiotics in Presence of Polyanions and Sputum of Patients with Cystic Fibrosis
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DOI：
10.1371/journal.pone.0005724
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发表时间：
2009-05-28
期刊：
影响因子：
3.7
通讯作者：
Omri, Abdelwahab
中科院分区：
文献类型：
--
作者：
Alipour, Misagh;Suntres, Zacharias E.;Omri, Abdelwahab
背景：比较妥布霉素脂质体或多粘菌素B对囊性纤维化（CF）痰液中铜绿假单胞菌的抑制作用，以及DNA、f -肌动蛋白、脂多糖（LPS）和脂质胆酸（LTA）等常见多阴离子成分对其的抑制作用。方法：分别由1,2-二肉豆醇- n-甘油-3-磷酸胆碱（DMPC）或1,2-二棕榈酰- n-甘油-3-磷酸胆碱（DPPC）和胆固醇（Chol）的混合物制备脂质体制剂。评价了不同生物环境下制剂的稳定性和在上述抑制因子或CF痰液存在下与常规制剂相比的抗菌活性。结果：制剂在各种条件下均稳定，与对照无显著差异。DNA/ f -肌动蛋白和LPS/LTA对抗生素制剂的抑制作用呈浓度依赖性。DNA/F-actin （125 ~ 1000 mg/L）和LPS/LTA （1 ~ 1000 mg/L）抑制常规妥布霉素的生物活性，而脂质体包裹的妥布霉素在更高浓度DNA/F-actin （500 ~ 1000 mg/L）和LPS/LTA （100 ~ 1000 mg/L）下被抑制。两种多粘菌素B制剂均未被DNA/ f -肌动蛋白灭活，但LPS/LTA（1至1000 mg/L）完全抑制了常规形式的药物，并且需要更高浓度的抑制剂（100至1000 mg/L）才能抑制脂质体包裹的多粘菌素B。与抑制因子（1000 mg/L）共孵育可提高常规（16倍）和脂质体（4倍）妥布霉素最低杀菌浓度（MBCs），而两种多粘菌素B制剂均被抑制64倍。结论：与常规抗生素相比，脂质体包埋可使抗生素抑制降低100倍，痰中内源性铜绿假单胞菌的CFU降低4倍，提示其在CF肺部感染中的潜在应用。
Background: To compare the effectiveness of liposomal tobramycin or polymyxin B against Pseudomonas aeruginosa in the Cystic Fibrosis (CF) sputum and its inhibition by common polyanionic components such as DNA, F-actin, lipopolysaccharides (LPS), and lipoteichoic acid (LTA).Methodology: Liposomal formulations were prepared from a mixture of 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) or 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and Cholesterol (Chol), respectively. Stability of the formulations in different biological milieus and antibacterial activities compared to conventional forms in the presence of the aforementioned inhibitory factors or CF sputum were evaluated.Results: The formulations were stable in all conditions tested with no significant differences compared to the controls. Inhibition of antibiotic formulations by DNA/F-actin and LPS/LTA was concentration dependent. DNA/F-actin (125 to 1000 mg/L) and LPS/LTA (1 to 1000 mg/L) inhibited conventional tobramycin bioactivity, whereas, liposome-entrapped tobramycin was inhibited at higher concentrations - DNA/F-actin (500 to 1000 mg/L) and LPS/LTA (100 to 1000 mg/L). Neither polymyxin B formulation was inactivated by DNA/F-actin, but LPS/LTA (1 to 1000 mg/L) inhibited the drug in conventional form completely and higher concentrations of the inhibitors (100 to 1000 mg/L) was required to inhibit the liposome-entrapped polymyxin B. Co-incubation with inhibitory factors (1000 mg/L) increased conventional (16-fold) and liposomal (4-fold) tobramycin minimum bactericidal concentrations (MBCs), while both polymyxin B formulations were inhibited 64-fold.Conclusions: Liposome-entrapment reduced antibiotic inhibition up to 100-fold and the CFU of endogenous P. aeruginosa in sputum by 4-fold compared to the conventional antibiotic, suggesting their potential applications in CF lung infections.