Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
German Center for Infection Research (DZIF), Site Hannover-Braunschweig, 38124 Braunschweig, Germany.
ACS Infect Dis. 2023 Mar 10;9(3):567-581. doi: 10.1021/acsinfecdis.2c00567. Epub 2023 Feb 10.
Achieving cellular uptake is a central challenge for novel antibiotics targeting Gram-negative bacterial pathogens. One strategy is to hijack the bacterial iron transport system by siderophore-antibiotic conjugates that are actively imported into the cell. This was realized with the MECAM-ampicillin conjugate LP-600 we recently reported that was highly active against . In the present study, we investigate a paradoxical regrowth of upon treatment of LP-600 at concentrations 16-32 times above the minimum inhibitory concentration (MIC). The phenomenon, coined "Eagle-effect" in other systems, was not due to resistance formation, and it occurred for the siderophore conjugate but not for free ampicillin. To investigate the molecular imprint of the Eagle effect, a combined transcriptome and untargeted metabolome analysis was conducted. LP-600 induced the expression of genes involved in iron acquisition, SOS response, and the e14 prophage upon regrowth conditions. The Eagle effect was diminished in the presence of sulbactam, which we ascribe to a putative synergistic antibiotic action but not to β-lactamase inhibition. The study highlights the relevance of the Eagle effect for siderophore conjugates. Through the first systematic -omics investigations, it also demonstrates that the Eagle effect manifests not only in a paradoxical growth but also in unique gene expression and metabolite profiles.
实现细胞摄取是针对革兰氏阴性细菌病原体的新型抗生素的核心挑战。一种策略是通过主动导入细胞的铁载体抗生素缀合物来劫持细菌的铁运输系统。我们最近报道的 MECAM-氨苄西林缀合物 LP-600 就是通过这种策略实现的，它对 具有高度活性。在本研究中，我们研究了在 LP-600 浓度高于最低抑菌浓度 (MIC)16-32 倍时， 发生的反常生长现象。这种现象在其他系统中被称为“鹰效”，不是由于耐药性的形成，而是由于铁载体缀合物而不是游离氨苄西林引起的。为了研究鹰效的分子印迹，我们进行了转录组和非靶向代谢组学联合分析。在再生条件下，LP-600 诱导了与铁摄取、SOS 反应和 e14 噬菌体相关的基因表达。在舒巴坦存在的情况下，鹰效减弱，我们将其归因于潜在的协同抗生素作用，而不是β-内酰胺酶抑制。该研究强调了鹰效对于铁载体缀合物的重要性。通过首次系统的 -omics 研究，它还表明鹰效不仅表现为反常生长，而且表现为独特的基因表达和代谢物图谱。
