Developments in Glycopeptide Antibiotics.
Developments in Glycopeptide Antibiotics.
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DOI：
10.1021/acsinfecdis.7b00258
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发表时间：
2018-05-11
影响因子：
5.3
通讯作者：
Cooper MA
中科院分区：
文献类型：
--
作者：
Blaskovich MAT;Hansford KA;Butler MS;Jia Z;Mark AE;Cooper MA
糖肽抗生素 (GPA) 是对抗耐药细菌的关键武器，万古霉素在首次推出 50 多年后仍然是治疗严重革兰氏阳性感染的主流疗法。已进入临床的新的、更有效的半合成衍生物，如达巴万星和奥利万星，具有优异的药代动力学和靶点参与特性，能够成功治疗万古霉素耐药感染。面对耐药性的发展，多重耐药 (MDR) 肺炎链球菌和耐甲氧西林金黄色葡萄球菌 (MRSA) 共同造成的感染数量是所有 MDR 革兰氏阴性菌感染总和的 20 倍，因此需要进一步改进，以确保为子孙后代充分维护革兰氏阳性菌库。在过去十年中，通过天然产物的全合成、半合成修饰或生物工程产生了一系列修饰糖肽。其中一些药物已经过广泛的表征，已证明体内功效、良好的 PK/PD 曲线，并且没有临床前毒性的报道；有些可能适合正式的临床前开发。天然产物单菌素、头孢菌素和β-内酰胺抗生素都催生了多代商业和临床上成功的半合成衍生物。同样，如果抗生素开发得到足够的资金和市场支持，下一代糖肽现在在技术上已经处于有利地位，可以进入临床。
Glycopeptide antibiotics (GPAs) are a key weapon in the fight against drug resistant bacteria, with vancomycin still a mainstream therapy against serious Gram-positive infections more than 50 years after it was first introduced. New, more potent semisynthetic derivatives that have entered the clinic, such as dalbavancin and oritavancin, have superior pharmacokinetic and target engagement profiles that enable successful treatment of vancomycin-resistant infections. In the face of resistance development, with multidrug resistant (MDR) S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) together causing 20-fold more infections than all MDR Gram-negative infections combined, further improvements are desirable to ensure the Gram-positive armamentarium is adequately maintained for future generations. A range of modified glycopeptides has been generated in the past decade via total syntheses, semisynthetic modifications of natural products, or biological engineering. Several of these have undergone extensive characterization with demonstrated in vivo efficacy, good PK/PD profiles, and no reported preclinical toxicity; some may be suitable for formal preclinical development. The natural product monobactam, cephalosporin, and β-lactam antibiotics all spawned multiple generations of commercially and clinically successful semisynthetic derivatives. Similarly, next-generation glycopeptides are now technically well positioned to advance to the clinic, if sufficient funding and market support returns to antibiotic development.
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