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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Development of a nebramine-cyclam conjugate as an antibacterial adjuvant to potentiate beta-lactam antibiotics against multidrug-resistant P. aeruginosa
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Development of a nebramine-cyclam conjugate as an antibacterial adjuvant to potentiate beta-lactam antibiotics against multidrug-resistant P. aeruginosa

机译：开发新溴 - 旋腔缀合物作为抗菌辅助的抗菌辅助抗生素抗生素对多药抗性P.铜绿假单胞菌的抗生素

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摘要

The beta-lactams are the most widely used class of antibiotics due to their safety, effectiveness, and spectrum of activity. As a result of their ubiquitous usage, there has been a steady rise in beta-lactam resistant Gram-negative bacteria, especially Pseudomonas aeruginosa, resulting in limited treatment options. P. aeruginosa can develop multidrug-resistant phenotypes using a multifaceted approach of beta-lactamase expression, decreased porin production and increased efflux. Current beta-lactamase inhibitors address drug hydrolyzing enzymes but may not be as effective in phenotypes with reduced permeability and/or overexpressed efflux pumps. Herein, we present the synthesis and biological evaluation of a nebramine-cyclam conjugate molecule that is able to potentiate beta-lactam antibiotics, as well as other legacy antibiotics, against P. aeruginosa in vitro. Combination studies show that this adjuvant is able to synergize with beta-lactams such as aztreonam and ceftazidime against multidrug-resistant and extremely drug-resistant clinical isolates through a hypothesized mechanism of outer membrane permeabilization. Importantly, the addition of low concentrations (8 mu M) of the nontoxic nebramine-cyclam conjugate is able to further potentiate existing beta-lactam/beta-lactamase inhibitor combinations in beta-lactamase-harboring P. aeruginosa strains. These data support a potential application of the nebramine-cyclam conjugate as an adjuvant for treating infections caused by P. aeruginosa strains that utilize multiple mechanisms of resistance.
机译：β-内酰胺是由于它们的安全性，有效性和活性谱，最广泛使用的抗生素。由于其普遍存在的使用，β-内酰胺抗革兰阴性细菌稳步上升，特别是假单胞菌铜绿假单胞菌，导致治疗方案有限。 P.铜绿假单胞菌可以使用多方面的β-内酰胺酶表达的方法开发多药抗性表型，降低孔隙产生和延长的流出。目前的β-内酰胺酶抑制剂地址药物水解酶，但可能在具有降低的渗透性和/或过表达的流出泵的表型中有效。在此，我们介绍了一种能够使β-内酰胺抗生素以及其他传统抗生素的β-内酰胺抗生素以及体外铜绿假单胞菌的合成和生物学评价。组合研究表明，这种佐剂能够通过β-内酰胺和头孢他啶的β-内酰胺，通过外膜透化机制通过假设机制来促进β-内酰胺和大肠杆菌抗多药和极其耐药性的临床分离物。重要的是，添加无毒新溴氨基 - 杉蛋白缀合物的低浓度（8μm）能够进一步增强现有的β-内酰胺/β-内酰胺酶抑制剂组合β-内酰胺酶宿毒性铜绿假单胞菌菌株。这些数据支持新溴氨基 - 循环缀合物作为治疗使用多种抗性机制的P.铜绿假单胞菌菌株引起的感染的佐剂。

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