Department of Chemical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA.
Department of Chemical Engineering, Pennsylvania State University, University Park, PA, 16802-4400, USA.
Biochem Biophys Res Commun. 2020 Mar 5;523(2):281-286. doi: 10.1016/j.bbrc.2020.01.102. Epub 2020 Jan 30.
Stress is ubiquitous for bacteria and can convert a subpopulation of cells into a dormant state known as persistence, in which cells are tolerant to antimicrobials. These cells revive rapidly when the stress is removed and are likely the cause of many recurring infections such as those associated with tuberculosis, cystic fibrosis, and Lyme disease. However, how persister cells are formed is not understood well. Here we propose the ppGpp ribosome dimerization persister (PRDP) model in which the alarmone guanosine pentaphosphate/tetraphosphate (henceforth ppGpp) generates persister cells directly by inactivating ribosomes via the ribosome modulation factor (RMF), the hibernation promoting factor (Hpf), and the ribosome-associated inhibitor (RaiA). We demonstrate that persister cells contain a large fraction of 100S ribosomes, that inactivation of RMF, HpF, and RaiA reduces persistence and increases single-cell persister resuscitation and that ppGpp has no effect on single-cell persister resuscitation. Hence, a direct connection between ppGpp and persistence is shown along with evidence of the importance of ribosome dimerization in persistence and for active ribosomes during resuscitation.
压力对细菌来说是普遍存在的，它可以将一部分细胞转化为休眠状态，称为持续存在，在这种状态下，细胞对抗微生物药物具有耐受性。当压力消除后，这些细胞会迅速复活，这很可能是许多反复感染的原因，如与结核病、囊性纤维化和莱姆病相关的感染。然而，持续存在细胞是如何形成的还不是很清楚。在这里，我们提出了 ppGpp 核糖体二聚体持续存在（PRDP）模型，其中警报素鸟苷五磷酸/四磷酸（以下简称 ppGpp）通过核糖体调节因子（RMF）、休眠促进因子（Hpf）和核糖体相关抑制剂（RaiA）直接使核糖体失活，从而产生持续存在细胞。我们证明持续存在细胞中含有大量的 100S 核糖体，RMF、HpF 和 RaiA 的失活会降低持续存在的概率，增加单细胞持续存在的复苏概率，并且 ppGpp 对单细胞持续存在的复苏没有影响。因此，显示了 ppGpp 与持续存在之间的直接联系，并提供了核糖体二聚化在持续存在和复苏过程中活跃核糖体中的重要性的证据。
