Biological Chemistry Group, Institute of Biology Leiden, Leiden University, 2333 Leiden, The Netherlands.
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 Utrecht, The Netherlands.
Molecules. 2021 Mar 30;26(7):1954. doi: 10.3390/molecules26071954.
The continued rise of antibiotic resistance threatens to undermine the utility of the world's current antibiotic arsenal. This problem is particularly troubling when it comes to Gram-negative pathogens for which there are inherently fewer antibiotics available. To address this challenge, recent attention has been focused on finding compounds capable of disrupting the Gram-negative outer membrane as a means of potentiating otherwise Gram-positive-specific antibiotics. In this regard, agents capable of binding to the lipopolysaccharide (LPS) present in the Gram-negative outer membrane are of particular interest as synergists. Recently, thrombin-derived C-terminal peptides (TCPs) were reported to exhibit unique LPS-binding properties. We here describe investigations establishing the capacity of TCPs to act as synergists with the antibiotics erythromycin, rifampicin, novobiocin, and vancomycin against multiple Gram-negative strains including polymyxin-resistant clinical isolates. We further assessed the structural features most important for the observed synergy and characterized the outer membrane permeabilizing activity of the most potent synergists. Our investigations highlight the potential for such peptides in expanding the therapeutic range of antibiotics typically only used to treat Gram-positive infections.
抗生素耐药性的持续上升威胁着削弱世界目前抗生素库的效用。当涉及到革兰氏阴性病原体时，这个问题尤其令人困扰，因为可供使用的抗生素本来就更少。为了解决这一挑战，最近人们的注意力集中在寻找能够破坏革兰氏阴性外膜的化合物，作为增强原本针对革兰氏阳性菌的抗生素的手段。在这方面，能够与革兰氏阴性外膜中存在的脂多糖（LPS）结合的试剂作为协同剂特别有意义。最近，有报道称凝血酶衍生的 C 端肽（TCP）具有独特的 LPS 结合特性。我们在这里描述了研究结果，这些研究结果证实了 TCP 能够与抗生素红霉素、利福平、新生霉素和万古霉素协同作用，针对多种革兰氏阴性菌株，包括多粘菌素耐药的临床分离株。我们进一步评估了对观察到的协同作用最重要的结构特征，并对最有效的协同剂的外膜通透活性进行了表征。我们的研究结果强调了这些肽在扩大通常仅用于治疗革兰氏阳性感染的抗生素治疗范围方面的潜力。
