Facile Synthesis and Metabolic Incorporation of m-DAP Bioisosteres Into Cell Walls of Live Bacteria.
Facile Synthesis and Metabolic Incorporation of m-DAP Bioisosteres Into Cell Walls of Live Bacteria.
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DOI：
10.1021/acschembio.0c00618
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发表时间：
2020-11-20
影响因子：
4
通讯作者：
Pires MM
中科院分区：
文献类型：
--
作者：
Apostolos AJ;Nelson JM;Silva JRA;Lameira J;Achimovich AM;Gahlmann A;Alves CN;Pires MM
细菌细胞壁含有肽聚糖（PG），这是一种支架，提供适当的刚性以抵抗内部渗透压的裂解，并保护细胞免受外部压力的影响。它由重复的糖单元组成，与细胞壁转肽酶（TP）高度交联的茎肽相连。虽然在茎肽第3位含有l -赖氨酸的PG片段更容易合成，但含有中二氨基亚苯甲酸（m-DAP）的PG片段则构成了严重的合成挑战。在此，我们描述了一种基于广泛可用的构建块来组装中半胱氨酸（m-CYT）的固相合成方案，该方案模仿了m-DAP的关键结构特征。为了证明对m-DAP的适当模仿，用m-CYT代替m-DAP合成细胞壁探针，并评估其在活细菌细胞中的代谢过程。我们发现基于m- cyt的细胞壁探针可以被内源性含有m-DAP的多种细菌的tp正确处理。此外，我们使用混合量子力学/分子力学（QM/MM）和分子动力学（MD）模拟来探索m-DAP类似物对PG交联的影响。结果表明，转肽酶的交联机制是一个协调一致的过程。我们预计，这种基于使用廉价和商业上可用的构建块的策略可以被广泛采用，为含有m-DAP的生物提供更大的PG模拟物的可及性。
Bacterial cell walls contain peptidoglycan (PG), a scaffold that provides proper rigidity to resist lysis from internal osmotic pressure and a barrier to protect cells against external stressors. It consists of repeating sugar units with a linkage to a stem peptide that becomes highly crosslinked by cell wall transpeptidases (TP). While synthetic PG fragments containing L-Lysine in the 3rd position on the stem peptide are easier to access, those with meso-diaminopimelic acid (m-DAP) pose a severe synthetic challenge. Herein, we describe a solid phase synthetic scheme based on widely available building blocks to assemble meso-cystine (m-CYT), which mimics key structural features of m-DAP. To demonstrate proper mimicry of m-DAP, cell wall probes were synthesized with m-CYT in place of m-DAP and evaluated for their metabolic processing in live bacterial cells. We found that m-CYT-based cell wall probes were properly processed by TPs in various bacterial species that endogenously contain m-DAP in their PG. Additionally, we have used hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) and Molecular Dynamics (MD) simulations to explore the influence of m-DAP analogs on the PG crosslinking. The results showed that crosslinking mechanism of transpeptidases occurred through a concerted process. We anticipate that this strategy, which is based on the use of inexpensive and commercially available building blocks, can be widely adopted to provide greater accessibility of PG mimics for m-DAP containing organisms.
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DOI：
10.1002/anie.201206749
发表时间：
2012-12-07
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Kuru E;Hughes HV;Brown PJ;Hall E;Tekkam S;Cava F;de Pedro MA;Brun YV;VanNieuwenhze MS
通讯作者：
VanNieuwenhze MS
影响因子：
3.2
作者：
Bernard, Elvis;Rolain, Thomas;Chapot-Chartier, Marie-Pierre
通讯作者：
Chapot-Chartier, Marie-Pierre
影响因子：
3.2
作者：
Cobb, Steven L.;Vederas, John C.
通讯作者：
Vederas, John C.
影响因子：
3.2
作者：
Diaper, CM;Sutherland, A;Vederas, JC
通讯作者：
Vederas, JC
影响因子：
3.5
作者：
Denoel, Thibaut;Zervosen, Astrid;Luxen, Andre
通讯作者：
Luxen, Andre