Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Microbe-Host Interactions Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Cell Rep. 2019 Feb 19;26(8):2009-2018.e6. doi: 10.1016/j.celrep.2019.01.089.
Acinetobacter baumannii is an important nosocomial pathogen capable of causing wound infections, pneumonia, and bacteremia. During infection, A. baumannii must acquire Zn to survive and colonize the host. Vertebrates have evolved mechanisms to sequester Zn from invading pathogens by a process termed nutritional immunity. One of the most upregulated genes during Zn starvation encodes a putative cell wall-modifying enzyme which we named ZrlA. We found that inactivation of zrlA diminished growth of A. baumannii during Zn starvation. Additionally, this mutant strain displays increased cell envelope permeability, decreased membrane barrier function, and aberrant peptidoglycan muropeptide abundances. This altered envelope increases antibiotic efficacy both in vitro and in an animal model of A. baumannii pneumonia. These results establish ZrlA as a crucial link between nutrient metal uptake and cell envelope homeostasis during A. baumannii pathogenesis, which could be targeted for therapeutic development.
鲍曼不动杆菌是一种重要的医院获得性病原体，能够引起伤口感染、肺炎和菌血症。在感染过程中，鲍曼不动杆菌必须获取锌才能存活并在宿主中定植。脊椎动物已经进化出通过营养免疫的过程来从入侵的病原体中隔离锌的机制。在缺锌时最上调的基因之一编码一种假定的细胞壁修饰酶，我们将其命名为 ZrlA。我们发现，zrlA 的失活减少了鲍曼不动杆菌在缺锌时的生长。此外，该突变株表现出增加的细胞包膜通透性、降低的膜屏障功能和异常的肽聚糖 muropeptide 丰度。这种改变的包膜增加了抗生素在体外和鲍曼不动杆菌肺炎动物模型中的疗效。这些结果确立了 ZrlA 作为鲍曼不动杆菌发病机制中营养金属摄取和细胞包膜动态平衡之间的关键联系，这可能成为治疗开发的目标。
