Competing off-loading mechanisms of meropenem from an l,d-transpeptidase reduce antibiotic effectiveness.
Competing off-loading mechanisms of meropenem from an l,d-transpeptidase reduce antibiotic effectiveness.
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L,D-转肽酶的美罗培南竞争性卸载机制会降低抗生素的有效性。
DOI：
10.1073/pnas.2008610118
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发表时间：
2021
影响因子：
11.1
通讯作者：
Townsend,CraigA
中科院分区：
文献类型：
--
作者：
Zandi,TrevorA;Townsend,CraigA
β-内酰胺抗生素的碳青霉烯家族显示出非常广谱的杀菌活性，例如美罗培南在肺结核患者中的II期临床试验成功，肺结核是一种破坏性疾病，β-内酰胺药物在历史上一直是众所周知的无效。l，d-转肽酶（Ldts）是细菌细胞壁生物合成的关键药物靶标，仅被碳青霉烯和青霉烯类结构有效抑制，其发现和验证为第一批抗结核β-内酰胺类药物的有效性提供了酶学基础。数十年的研究已经描绘了β-内酰胺抑制其典型靶点青霉素结合蛋白的机制;然而，关于药物设计中的Ldt抑制机制，特别是动力学行为和效力的优化，仍然存在悬而未决的问题。我们研究了分枝杆菌Ldt抑制的关键特征，并在此证明共价抑制剂美罗培南通过高能硫酯加合物从半胱氨酸转肽酶LdtMt 2进行可逆反应和非水解卸载反应。下一代碳青霉烯优化策略应最大限度地减少Ldt加合物的非生产性机制导致的加合物损失，从而降低有效药物浓度。
The carbapenem family of β-lactam antibiotics displays a remarkably broad spectrum of bactericidal activity, exemplified by meropenem’s phase II clinical trial success in patients with pulmonary tuberculosis, a devastating disease for which β-lactam drugs historically have been notoriously ineffective. The discovery and validation ofl,d-transpeptidases (Ldts) as critical drug targets of bacterial cell-wall biosynthesis, which are only potently inhibited by the carbapenem and penem structural classes, gave an enzymological basis for the effectiveness of the first antitubercular β-lactams. Decades of study have delineated mechanisms of β-lactam inhibition of their canonical targets, the penicillin-binding proteins; however, open questions remain regarding the mechanisms of Ldt inhibition that underlie programs in drug design, particularly the optimization of kinetic behavior and potency. We have investigated critical features of mycobacterial Ldt inhibition and demonstrate here that the covalent inhibitor meropenem undergoes both reversible reaction and nonhydrolytic off-loading reactions from the cysteine transpeptidase LdtMt2through a high-energy thioester adduct. Next-generation carbapenem optimization strategies should minimize adduct loss from unproductive mechanisms of Ldt adducts that reduce effective drug concentration.