Persisters包含一组具有多药耐受性的表型异质性代谢静止细菌,并有助于慢性感染的顽抗。尽管最近的工作表明,毒素-抗毒素(TA)系统HipAB依赖于严格的反应效应子(p)ppGppin持久性形成,其他坚持途径是否也依赖于严格的反应尚未探索。在这里,我们检查了(p)ppGpp与15个常见的持久性基因(dnaK,clpB,rpos,pspF,tnaA,sucB,ssrA,SMPB,recA,umuD,uvra,hipa,mqsR,relie,dinJ)使用大肠杆菌作为模型。通过比较野生型及其单基因敲除和双敲除突变体与relA的坚持水平,我们将它们的相互作用分为五种类型,即A“依赖”(dnaK,recA),B“正强化”(rpos,pspF,ssrA,recA),C“拮抗”(clpB,sucB,umuD,uvra,hipa,mqsR,relie,dinJ),D“上位”(clpB,rpos,tnaA,ssrA,SMPB,hipA),和E“不相关”(dnaK,clpB,rpos,tnaA,sucB,SMPB,umuD,uvra,hipa,mqsR,relie,dinJ).我们发现持久性基因相互作用与细菌培养年龄密切相关,细胞浓度(稀释与未稀释培养),和药物分类,相同的基因可能属于不同的抗生素组,培养年龄或细胞浓度。一起,这项研究是首次尝试系统地描述不同持久性机制之间的复杂关系,因此在持久性基因网络相互作用的水平上为持久性现象的复杂性提供了新的见解。
Persisters comprise a group of phenotypically heterogeneous metabolically quiescent bacteria with multidrug tolerance and contribute to the recalcitrance of chronic infections. Although recent work has shown that toxin-antitoxin (TA) system HipAB depends on stringent response effector (p)ppGppin persister formation, whether other persister pathways are also dependent on stringent response has not been explored. Here we examined the relationship of (p)ppGpp with 15 common persister genes (dnaK, clpB, rpoS, pspF, tnaA, sucB, ssrA, smpB, recA, umuD, uvrA, hipA, mqsR, relE, dinJ) using Escherichia coli as a model. By comparing the persister levels of wild type with their single gene knockout and double knockout mutants with relA, we divided their interactions into five types, namely A \"dependent\" (dnaK, recA), B \"positive reinforcement\" (rpoS, pspF, ssrA, recA), C \"antagonistic\" (clpB, sucB, umuD, uvrA, hipA, mqsR, relE, dinJ), D \"epistasis\" (clpB, rpoS, tnaA, ssrA, smpB, hipA), and E \"irrelevant\" (dnaK, clpB, rpoS, tnaA, sucB, smpB, umuD, uvrA, hipA, mqsR, relE, dinJ). We found that the persister gene interactions are intimately dependent on bacterial culture age, cell concentrations (diluted versus undiluted culture), and drug classifications, where the same gene may belong to different groups with varying antibiotics, culture age or cell concentrations. Together, this study represents the first attempt to systematically characterize the intricate relationships among the different mechanisms of persistence and as such provide new insights into the complexity of the persistence phenomenon at the level of persister gene network interactions.