Inhibition of β-lactamase function by de novo designed peptide.
Inhibition of β-lactamase function by de novo designed peptide.
复制标题
DOI：
10.1371/journal.pone.0290845
复制
发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
抗菌素耐药性是一个重大的公共卫生问题，现在被描述为一种“无声的大流行”。全球抗菌素耐药性的负担需要新的抗菌药治疗，特别是对最具挑战性的多重耐药细菌。细菌产生抗药性的机制有多种，包括β-内酰胺酶的表达，外排泵的过度表达，通过下调β-内酰胺类进入所需的孔蛋白而降低细胞通透性，或青霉素结合蛋白的修饰。β-内酰胺类抗生素被β-内酰胺酶灭活是细菌对这些药物耐药的最常见机制。虽然临床上有几种有效的β-内酰胺酶小分子抑制剂，如克拉维酸和阿维巴坦，但它们只作用于特定的A、C类和一些D类酶。目前，临床批准的抑制剂均不能有效抑制B类金属β-内酰胺酶。此外，据报道，在几种细菌中，对这些抑制剂的耐药性增加。这项研究的目的是使用共振识别模型(RRM)作为一种新的策略来抑制/调节特定的抗菌素耐药靶点。RRM是一种生物物理方法，它分析自由电子的能量分布，并假设这种能量分布的光谱与相关的蛋白质生物活性之间存在显著的相关性。在这项研究中，我们使用Rrm的概念来评估一组22个β-内酰胺酶蛋白质的结构-功能性质，并设计了具有所需Rrm光谱周期(频率)的30聚体多肽来作为β-内酰胺酶抑制剂。与对照组相比，我们的结果显示，来自大肠埃希菌和阴沟肠杆菌的A类β-内酰胺酶被100%抑制。综上所述，RRM模型很可能被用作设计任何特定类别的β-内酰胺酶抑制剂的一种有前途的方法。这可能会为对抗抗菌素耐药性开辟新的方向。
Antimicrobial resistance is a great public health concern that is now described as a “silent pandemic”. The global burden of antimicrobial resistance requires new antibacterial treatments, especially for the most challenging multidrug-resistant bacteria. There are various mechanisms by which bacteria develop antimicrobial resistance including expression of β-lactamase enzymes, overexpression of efflux pumps, reduced cell permeability through downregulation of porins required for β-lactam entry, or modifications in penicillin-binding proteins. Inactivation of the β-lactam antibiotics by β-lactamase enzymes is the most common mechanism of bacterial resistance to these agents. Although several effective small-molecule inhibitors of β-lactamases such as clavulanic acid and avibactam are clinically available, they act only on selected class A, C, and some class D enzymes. Currently, none of the clinically approved inhibitors can effectively inhibit Class B metallo-β-lactamases. Additionally, there is increased resistance to these inhibitors reported in several bacteria. The objective of this study is to use the Resonant Recognition Model (RRM), as a novel strategy to inhibit/modulate specific antimicrobial resistance targets. The RRM is a bio-physical approach that analyzes the distribution of energies of free electrons and posits that there is a significant correlation between the spectra of this energy distribution and related protein biological activity. In this study, we have used the RRM concept to evaluate the structure-function properties of a group of 22 β-lactamase proteins and designed 30-mer peptides with the desired RRM spectral periodicities (frequencies) to function as β-lactamase inhibitors. In contrast to the controls, our results indicate 100% inhibition of the class A β-lactamases from Escherichia coli and Enterobacter cloacae. Taken together, the RRM model can likely be utilized as a promising approach to design β-lactamase inhibitors for any specific class. This may open a new direction to combat antimicrobial resistance.
登录
查看更多内容
影响因子：
5.2
作者：
Lin J;Nishino K;Roberts MC;Tolmasky M;Aminov RI;Zhang L
通讯作者：
Zhang L
影响因子：
11.5
作者：
Bebrone, Carine;Lassaux, Patricia;Galleni, Moreno
通讯作者：
Galleni, Moreno
影响因子：
4.2
作者：
Almansour, Nahlah M.;Pirogova, Elena;Istivan, Taghrid S.
通讯作者：
Istivan, Taghrid S.
影响因子：
4.9
作者：
Boyd, Sara E.;Livermore, David M.;Hope, William W.
通讯作者：
Hope, William W.
影响因子：
5.2
作者：
通讯作者：
--