青霉素结合蛋白 3 与五种β-内酰胺抗生素复合物的结构揭示了失活机制。

Structures of Penicillin-Binding Protein 3 in Complex with Five -Lactam Antibiotics Reveal Mechanism of Inactivation.

机构信息

Key Laboratory of Biomarker Based Rapid-detection Technology for Food Safety of Henan Province, Xuchang University, Xuchang, Henan, China (Z.L., A.Z.); College of Life Sciences (Z.L., H.W., W.Z. and Z.R.) and College of Pharmacy (X.L., C.Y.), Nankai University, Tianjin, China; School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia (L.G.); School of Life Sciences, Tianjin University, Tianjin, China (H.Y.); University of Oxford, Chemistry Research Laboratory, Oxford, United Kingdom (C.J.S.); National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China (Z.R.); and Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China (Z.R.).

出版信息

Mol Pharmacol. 2020 Apr;97(4):287-294. doi: 10.1124/mol.119.118042. Epub 2020 Feb 21.

DOI:10.1124/mol.119.118042

PMID:32086254

Abstract

Because of -lactamase-mediated resistance, -lactam antibiotics were long considered ineffective drugs for tuberculosis (TB) treatment. However, some -lactams, including meropenem and faropenem, are being re-evaluated in patients infected with TB. Penicillin-binding protein (PBP) 3, or ftsI, is an essential transpeptidase in required for cell division, and thus it is an important drug target. Structures of apo PBP3 and of complexes with five -lactams, including meropenem and faropenem, reveal how they cause inactivation via formation of hydrolytically stable acyl-enzyme complexes. The structures reveal unique features of the antibiotic interactions, both in terms of differences in their binding to PBP3 and in comparison with structures of other PBPs and serine -lactamases, including the tautomerization status of the carbapenem-derived acyl-enzyme complexes. The results suggest that rather than PBP inhibitors developed for other infections will work against TB, work should focus on developing PBP inhibitors for treating TB. SIGNIFICANCE STATEMENT: The structures of penicillin-binding protein 3, an essential protein in , in complex with a number of widely used -lactam antibiotics (e.g., meropenem, aztreonam, and amoxicillin) were solved. These data provide new insights for next-generation rational approaches to design tuberculosis (TB)-specific -lactam or nonlactam antibiotics. This manuscript is a seminal article in the field of anti-TB drug discovery and suitable for the broad readership.

摘要

由于β-内酰胺酶介导的耐药性，β-内酰胺类抗生素长期以来被认为对结核病（TB）治疗无效。然而，一些β-内酰胺类药物，包括美罗培南和法罗培南，正在感染结核病的患者中重新评估。青霉素结合蛋白（PBP）3，或 ftsI，是细胞分裂所必需的转肽酶，因此它是一个重要的药物靶点。apo PBP3 的结构和与五种β-内酰胺类药物（包括美罗培南和法罗培南）的复合物结构揭示了它们如何通过形成水解稳定的酰基-酶复合物而导致失活。这些结构揭示了抗生素相互作用的独特特征，包括它们与 PBP3 的结合差异以及与其他 PBPs 和丝氨酸β-内酰胺酶的结构比较，包括碳青霉烯衍生的酰基-酶复合物的互变异构状态。结果表明，针对其他感染开发的而不是针对结核病的 PBP 抑制剂将起作用，应专注于开发针对结核病的 PBP 抑制剂。意义陈述：与许多广泛使用的β-内酰胺抗生素（例如美罗培南、氨曲南和阿莫西林）结合的青霉素结合蛋白 3 的结构已被解决。这些数据为设计针对结核病（TB）的特异性β-内酰胺或非内酰胺抗生素的下一代合理方法提供了新的见解。这篇论文是抗结核病药物发现领域的一篇重要文章，适合广泛的读者阅读。