Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.
mBio. 2020 Jan 21;11(1):e03117-19. doi: 10.1128/mBio.03117-19.
Antimicrobial resistance is a major health threat as it limits treatment options for infection. At the forefront of this serious issue is , a Gram-negative opportunistic pathogen that exhibits the remarkable ability to resist antibiotics through multiple mechanisms. As bacterial ribosomes represent a target for multiple distinct classes of existing antimicrobial agents, we here use single-particle cryo-electron microscopy (cryo-EM) to elucidate five different structural states of the ribosome, including the 70S, 50S, and 30S forms. We also determined interparticle motions of the 70S ribosome in different tRNA bound states using three-dimensional (3D) variability analysis. Together, our structural data further our understanding of the ribosome from and other Gram-negative pathogens and will enable structure-based drug discovery to combat antibiotic-resistant bacterial infections. is a severe nosocomial threat largely due to its intrinsic antibiotic resistance and remarkable ability to acquire new resistance determinants. The bacterial ribosome serves as a major target for modern antibiotics and the design of new therapeutics. Here, we present cryo-EM structures of the 70S ribosome, revealing several unique species-specific structural features that may facilitate future drug development to combat this recalcitrant bacterial pathogen.
抗菌药物耐药性是一个主要的健康威胁，因为它限制了感染的治疗选择。在这个严重问题的前沿，是一种革兰氏阴性机会性病原体，它通过多种机制表现出显著的抗抗生素能力。由于细菌核糖体是多种不同类别的现有抗菌药物的靶标，我们在这里使用单颗粒低温电子显微镜 (cryo-EM) 来阐明核糖体的五种不同结构状态，包括 70S、50S 和 30S 形式。我们还使用三维（3D）可变性分析确定了不同 tRNA 结合状态下 70S 核糖体的颗粒间运动。总之，我们的结构数据进一步加深了我们对来自 和其他革兰氏阴性病原体的核糖体的理解，并将能够基于结构的药物发现来对抗抗药性细菌感染。 是一种严重的医院获得性威胁，主要是由于其内在的抗生素耐药性和获得新的耐药决定因素的能力。细菌核糖体是现代抗生素和新疗法设计的主要靶标。在这里，我们展示了 70S 核糖体的 cryo-EM 结构，揭示了几种独特的种特异性结构特征，这可能有助于未来开发对抗这种顽固细菌病原体的药物。
