Department of Pharmaceutics and Nanotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
J Pharm Pharm Sci. 2018;22(1):10-21. doi: 10.18433/jpps29659.
The antibacterial activity of some antibiotics is specific to either Gram-positive or Gram-negative bacteria. There are different mechanisms behind such insensitivities like inability of antibiotics to permeate through some bacterial membranes, as is the case for vancomycin in Gram-negative bacteria. The present investigation tries to overcome this problem by dendrimers, in order to make Gram-negative bacteria responsive to vancomycin.
The effects of generations 3 (G3) and 5 (G5) polyamidoamine amine-terminated dendrimers (NH2-PAMAM), on the antibacterial activity of vancomycin, were evaluated. Vancomycin-PAMAM dendrimers complexes were prepared and their antibacterial activities were evaluated by determination of their "minimum inhibitory concentration (MIC)", "minimum bactericidal concentration" and "fractional inhibitory concentration index" values against two Gram-positive and four Gram-negative bacteria, using broth micro-dilution method. The complexation of vancomycin and dendrimers was also assessed by in vitro release studies across dialysis tubing using a developed HPLC method.
Results showed that vancomycin solution was effective against Gram-positive bacteria, but, was not effective in Gram-negative ones. Vancomycin-PAMAM dendrimers exhibited significant antibacterial efficacy against Gram-negative bacteria resulting in a decline of vancomycin MIC values by about 2, 2, 4 and 64 times in E. coli, K. pneumonia, S. typhimurium and P. aeruginosa, respectively. Results also showed that enhanced effect by G5 is more than G3. Dendrimers did not affect antibacterial activity of vancomycin in Gram-positive bacteria, as no permeation problem exists here.
The present study revealed that both G3 and G5 cationic PAMAM dendrimers are able to make Gram-negative bacteria sensitive to vancomycin, resulting in decline of MIC values up to 64 times, possibly by increasing its permeation through bacterial membrane. These results look promising for broadening the antibacterial spectrum of vancomycin and such a strategy might be used for increasing the overall life of antibiotics.
一些抗生素的抗菌活性是针对革兰氏阳性菌或革兰氏阴性菌的。这种不敏感性背后有不同的机制，比如抗生素无法穿透某些细菌的细胞膜，万古霉素在革兰氏阴性菌中就是这种情况。本研究试图通过树枝状大分子克服这一问题，使革兰氏阴性菌对万古霉素敏感。
评估了第 3 代（G3）和第 5 代（G5）聚酰胺胺胺端树枝状大分子（NH2-PAMAM）对万古霉素抗菌活性的影响。制备了万古霉素-PAMAM 树枝状大分子复合物，并通过肉汤微量稀释法测定其“最低抑菌浓度（MIC）”、“最低杀菌浓度”和“抑菌浓度指数”值，评估其对两种革兰氏阳性菌和四种革兰氏阴性菌的抗菌活性。还通过体外释放研究评估了万古霉素和树枝状大分子的复合物，该研究使用了一种开发的 HPLC 方法，通过透析管进行。
结果表明，万古霉素溶液对革兰氏阳性菌有效，但对革兰氏阴性菌无效。万古霉素-PAMAM 树枝状大分子对革兰氏阴性菌表现出显著的抗菌功效，使大肠杆菌、肺炎克雷伯菌、鼠伤寒沙门氏菌和铜绿假单胞菌的万古霉素 MIC 值分别下降了约 2、2、4 和 64 倍。结果还表明，G5 的增强效果优于 G3。树枝状大分子对革兰氏阳性菌的万古霉素抗菌活性没有影响，因为这里不存在渗透问题。
本研究表明，第 3 代和第 5 代阳离子 PAMAM 树枝状大分子均能使革兰氏阴性菌对万古霉素敏感，使 MIC 值下降高达 64 倍，可能是通过增加其穿透细菌细胞膜的能力。这些结果为扩大万古霉素的抗菌谱提供了希望，这种策略可能用于延长抗生素的整体寿命。
