Schmidt Martin, Bast Livia K, Lanfer Franziska, Richter Lena, Hennes Elisabeth, Seymen Rana, Krumm Christian, Tiller Joerg C
Biomaterials and Polymer Science, Department of Bio- and Chemical Engineering, TU Dortmund , Emil-Figge-Straße 66, 44227 Dortmund, Germany.
Bioconjug Chem. 2017 Sep 20;28(9):2440-2451. doi: 10.1021/acs.bioconjchem.7b00424. Epub 2017 Sep 6.
The conjugation of antibiotics with polymers is rarely done, but it might be a promising alternative to low-molecular-weight derivatization. The two penicillins penicillin G (PenG) and penicillin V (PenV) were attached to the end groups of different water-soluble poly(2-oxazoline)s (POx) via their carboxylic acid function. This ester group was shown to be more stable against hydrolysis than the β-lactam ring of the penicillins. The conjugates are still antimicrobially active and up to 20 times more stable against penicillinase catalyzed hydrolysis. The antibiotic activity of the conjugates against Staphylococcus aureus in the presence of penicillinase is up to 350 times higher compared with the free antibiotics. Conjugates with a second antimicrobial function, a dodecyltrimethylammonium group (DDA-X), at the starting end of the PenG and PenV POx conjugates are more antimicrobially active than the conjugates without DDA-X and show high activity in the presence of penicillinase. For example, the conjugates DDA-X-PEtOx-PenG and DDA-X-PEtOx-PenV are 200 to 350 times more active against S. aureus in the presence of penicillinase and almost as effective as the penicillinase stable cloxacollin (Clox) under these conditions. These conjugates show even greater activity compared to cloxacollin without this enzyme present. Further, both conjugates kill Escherichia coli more effectively than PenG and Clox.
抗生素与聚合物的共轭结合很少进行，但它可能是低分子量衍生化的一种有前景的替代方法。两种青霉素，即青霉素G（PenG）和青霉素V（PenV），通过它们的羧酸官能团连接到不同水溶性聚（2-恶唑啉）（POx）的端基上。结果表明，这种酯基比青霉素的β-内酰胺环对水解更稳定。这些共轭物仍然具有抗菌活性，并且对青霉素酶催化的水解稳定性提高了20倍。在有青霉素酶存在的情况下，共轭物对金黄色葡萄球菌的抗生素活性比游离抗生素高350倍。在PenG和PenV POx共轭物起始端带有第二种抗菌功能基团十二烷基三甲基铵基团（DDA-X）的共轭物，比没有DDA-X的共轭物抗菌活性更高，并且在有青霉素酶存在时表现出高活性。例如，共轭物DDA-X-PEtOx-PenG和DDA-X-PEtOx-PenV在有青霉素酶存在时对金黄色葡萄球菌的活性比游离抗生素高200至350倍，并且在这些条件下几乎与对青霉素酶稳定的氯唑西林（Clox）一样有效。与没有这种酶时相比，这些共轭物与氯唑西林相比表现出更大的活性。此外，两种共轭物对大肠杆菌的杀灭效果都比PenG和Clox更有效。
