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Inhibition Mechanism of Class D β-Lactamases by Avibactam
ACS Catalysis ( IF 12.9 ) Pub Date : 2022-08-08 , DOI: 10.1021/acscatal.2c02693
Vaishali Thakkur 1 , Chandan Kumar Das 1 , Nisanth N. Nair 1
Affiliation  

Escalation of antibiotic resistance due to class D β-lactamases (DBLs) carrying bacteria is a matter of grave concern. This class of enzymes can efficiently hydrolyze the carbapenem group of antibiotics that are the last-reserved therapeutics for infections caused by multidrug-resistant bacteria. The development of efficient inhibitors against DBLs calls for a molecular-level understanding of the hydrolysis mechanism. Here, we investigate the mechanism of inhibition of OXA-48 DBL enzyme by one of the diazobicyclooctane class of inhibitors, namely avibactam, through molecular dynamics simulations and free energy calculations. Hydrolysis as well as inhibition mechanisms are expected to be intricate due to the presence of N-carbamylated lysine (Lys73), multiple acidic and basic active site residues, and active site water molecules. Our extensive mechanistic study characterizes the most probable reaction route and critical reaction intermediates starting from the acylation to the full hydrolysis of the covalent intermediate. This study discerns the residues that act as the general bases at different steps. Free energies and reaction intermediate structures are corroborated with the available experimental kinetics data and crystal structures. We also simulated the deacylation of a β-lactam drug, namely meropenem, which is known to be hydrolyzed efficiently by the enzyme. By comparing the mechanism of meropenem hydrolysis with that of avibactam, our study reveals the important chemical features that are useful for designing inhibitors.

中文翻译:

Avibactam对D类β-内酰胺酶的抑制机制

由于携带细菌的 D 类 β-内酰胺酶 (DBL) 导致的抗生素耐药性升级是一个严重关切的问题。这类酶可以有效地水解碳青霉烯类抗生素,这些抗生素是由耐多药细菌引起的感染的最后保留疗法。开发针对 DBL 的有效抑制剂需要对水解机制进行分子水平的理解。在这里,我们通过分子动力学模拟和自由能计算研究了重氮双环辛烷类抑制剂之一,即阿维巴坦抑制 OXA-48 DBL 酶的机制。由于存在 N-氨甲酰化赖氨酸 (Lys73)、多个酸性和碱性活性位点残基以及活性位点水分子,预计水解和抑制机制将是复杂的。我们广泛的机理研究描述了从酰化到共价中间体完全水解的最可能的反应路线和关键反应中间体。这项研究识别了在不同步骤中充当一般碱基的残基。可用的实验动力学数据和晶体结构证实了自由能和反应中间结构。我们还模拟了一种 β-内酰胺类药物,即美罗培南的脱酰作用,已知它可以被酶有效水解。通过比较美罗培南与阿维巴坦的水解机制,我们的研究揭示了可用于设计抑制剂的重要化学特征。
更新日期:2022-08-08
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