Malabarba A, Trani A, Strazzolini P, Cietto G, Ferrari P, Tarzia G, Pallanza R, Berti M
Merrell Dow Research Institute, Lepetit Research Center, Varese, Italy.
J Med Chem. 1989 Nov;32(11):2450-60. doi: 10.1021/jm00131a007.
The condensation of the carboxyl function of teicoplanin A2 (CTA) and its acidic hydrolysis pseudoaglycons (TB, TC) and aglycon (TD) with amines carrying various functional groups and chains produced amide derivatives with different isoelectric points and lipophilicities. Amide formation did not affect the ability of these compounds to bind to Ac2-L-Lys-D-Ala-D-Ala, a model for the natural peptide binding site in bacterial cell walls. The antimicrobial activities of teicoplanin amides were found to depend mostly on their ionic and lipophilic character and on the type and number of sugars present. Positively charged amides were generally more in vitro active than the respective unmodified antibiotics against Gram-positive organisms. In particular, most basic amides of CTA were markedly more active than teicoplanin against coagulase-negative staphylococci. A few amides of TC and most of those of TD also showed a certain activity against Gram-negative bacteria. In experimental Streptococcus pyogenes septicemia in the mouse, some basic amides were more active than the parent teicoplanins when administered subcutaneously. Some of those of CTA were also slightly more effective than teicoplanin by oral route.
替考拉宁A2（CTA）及其酸性水解假苷元（TB、TC）和苷元（TD）的羧基功能与带有各种官能团和链的胺缩合，生成了具有不同等电点和亲脂性的酰胺衍生物。酰胺的形成并不影响这些化合物与Ac2-L-赖氨酸-D-丙氨酸-D-丙氨酸结合的能力，Ac2-L-赖氨酸-D-丙氨酸-D-丙氨酸是细菌细胞壁中天然肽结合位点的模型。发现替考拉宁酰胺的抗菌活性主要取决于其离子和亲脂特性以及所含糖的类型和数量。带正电荷的酰胺通常在体外比相应的未修饰抗生素对革兰氏阳性菌更具活性。特别是，CTA的大多数碱性酰胺对凝固酶阴性葡萄球菌的活性明显高于替考拉宁。TC的一些酰胺和TD的大多数酰胺对革兰氏阴性菌也表现出一定活性。在小鼠实验性化脓性链球菌败血症中，一些碱性酰胺皮下给药时比母体替考拉宁更具活性。CTA的一些酰胺经口服给药时也比替考拉宁略有效。
