Morris Michael A, Vallmitjana Alexander, Grein Fabian, Schneider Tanja, Arts Melina, Jones Chelsea R, Nguyen Betty T, Hashemian Mohammad H, Malek Melody, Gratton Enrico, Nowick James S
Department of Chemistry, University of California, Irvine Irvine California 92697 USA
Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine Irvine California 92697 USA.
Chem Sci. 2022 May 13;13(26):7747-7754. doi: 10.1039/d2sc01388f. eCollection 2022 Jul 6.
Teixobactin has been the source of intensive study and interest as a promising antibiotic, because of its excellent activity against drug-resistant Gram-positive pathogens and its novel but not yet fully understood mechanism of action that precludes drug resistance. Recent studies have demonstrated that the mode of action of teixobactin is more complicated than initially thought, with supramolecular assembly of the antibiotic appearing to play a critical role in the binding process. Further studies of the interactions of teixobactin with bacteria and its molecular targets offer the promise of providing deeper insights into its novel mechanism of action and guiding the design of additional drug candidates and analogues. The current study reports the preparation and study of teixobactin analogues bearing a variety of fluorophores. Structured illumination microscopy of the fluorescent teixobactin analogues with enables super-resolution visualization of the interaction of teixobactin with bacterial cell walls and permits the observation of aggregated clusters of the antibiotic on the bacteria. Förster resonance energy transfer (FRET) microscopy further elucidates the supramolecular assembly by showing that fluorescent teixobactin molecules co-localize within a few nanometers on . Fluorescence microscopy over time with a fluorescent teixobactin analogue and propidium iodide in reveals a correlation between cell death and binding of the antibiotic to cellular targets, followed by lysis of cells. Collectively, these studies provide new insights into the binding of teixobactin to Gram-positive bacteria, its supramolecular mechanism of action, and the lysis of bacteria that follows.
作为一种有前景的抗生素，替考拉宁一直是深入研究和关注的焦点，因为它对耐药革兰氏阳性病原体具有出色的活性，其作用机制新颖但尚未完全理解，这使得细菌难以产生耐药性。最近的研究表明，替考拉宁的作用方式比最初认为的更为复杂，抗生素的超分子组装似乎在结合过程中起关键作用。对替考拉宁与细菌及其分子靶点相互作用的进一步研究有望更深入地了解其新颖的作用机制，并指导设计更多的候选药物和类似物。本研究报告了带有各种荧光团的替考拉宁类似物的制备和研究。对荧光替考拉宁类似物进行结构光照显微镜观察，能够超分辨率可视化替考拉宁与细菌细胞壁的相互作用，并观察到抗生素在细菌上的聚集簇。Förster共振能量转移（FRET）显微镜通过显示荧光替考拉宁分子在几纳米内共定位，进一步阐明了超分子组装。用荧光替考拉宁类似物和碘化丙啶对 进行长时间荧光显微镜观察，揭示了细胞死亡与抗生素与细胞靶点结合之间的相关性，随后细胞发生裂解。总的来说，这些研究为替考拉宁与革兰氏阳性细菌的结合、其超分子作用机制以及随后的细菌裂解提供了新的见解。
