Salzer Andrea, Wolz Christiane
Interfaculty Institute of Microbiology and Infection Medicine, 72076 Tübingen, Germany.
Cluster of Excellence EXC 2124 "Controlling Microbes to Fight Infections", University of Tübingen, 72076 Tübingen, Germany.
Microlife. 2023 Mar 11;4:uqad009. doi: 10.1093/femsml/uqad009. eCollection 2023.
The stringent response and its signalling nucleotides, pppGpp and ppGpp, have been the subject of intense research since the discovery of (p)ppGpp in 1969. Recent studies have revealed that the downstream events that follow (p)ppGpp accumulation vary among species. Consequently, the stringent response as initially characterized in largely differs from the response in Firmicutes (Bacillota), wherein synthesis and degradation of the messengers (p)ppGpp are orchestrated by the bifunctional Rel enzyme with synthetase and hydrolase activity and the two synthetases SasA/RelP and SasB/RelQ. Here we will summarize recent studies supporting the role of (p)ppGpp in the development of antibiotic resistance and tolerance as well as survival under adverse environmental conditions in Firmicutes. We will also discuss the impact of elevated (p)ppGpp levels on the development of persister cells and the establishment of persistent infections. (p)ppGpp levels are usually tightly controlled to allow optimal growth under non-stressed conditions. Upon the onset of certain 'stringent conditions' the sudden increase in (p)ppGpp levels limits growth while exerting protective effects. In Firmicutes, the (p)ppGpp-mediated restriction of GTP accumulation is one major mechanism of protection and survival under stresses such as antibiotic exposure.
自1969年发现（p）ppGpp以来，严谨反应及其信号核苷酸pppGpp和ppGpp一直是深入研究的主题。最近的研究表明，（p）ppGpp积累后发生的下游事件在不同物种间存在差异。因此，最初在大肠杆菌中描述的严谨反应与厚壁菌门（芽孢杆菌纲）中的反应有很大不同，在厚壁菌门中，信使分子（p）ppGpp的合成和降解由具有合成酶和水解酶活性的双功能Rel酶以及两种合成酶SasA/RelP和SasB/RelQ协调。在此，我们将总结最近的研究，这些研究支持（p）ppGpp在厚壁菌门抗生素耐药性和耐受性发展以及在不利环境条件下生存中的作用。我们还将讨论（p）ppGpp水平升高对持留菌细胞形成和持续性感染建立的影响。（p）ppGpp水平通常受到严格控制，以允许在非应激条件下实现最佳生长。在某些“严格条件”开始时，（p）ppGpp水平的突然升高会限制生长，同时发挥保护作用。在厚壁菌门中，（p）ppGpp介导的GTP积累限制是在抗生素暴露等应激条件下保护和生存的一种主要机制。
