Department of Biology, Northeastern University, Antimicrobial Discovery Center, Boston, Massachusetts, United States of America.
PLoS Biol. 2010 Feb 23;8(2):e1000317. doi: 10.1371/journal.pbio.1000317.
Bacteria induce stress responses that protect the cell from lethal factors such as DNA-damaging agents. Bacterial populations also form persisters, dormant cells that are highly tolerant to antibiotics and play an important role in recalcitrance of biofilm infections. Stress response and dormancy appear to represent alternative strategies of cell survival. The mechanism of persister formation is unknown, but isolated persisters show increased levels of toxin/antitoxin (TA) transcripts. We have found previously that one or more components of the SOS response induce persister formation after exposure to a DNA-damaging antibiotic. The SOS response induces several TA genes in Escherichia coli. Here, we show that a knockout of a particular SOS-TA locus, tisAB/istR, had a sharply decreased level of persisters tolerant to ciprofloxacin, an antibiotic that causes DNA damage. Step-wise administration of ciprofloxacin induced persister formation in a tisAB-dependent manner, and cells producing TisB toxin were tolerant to multiple antibiotics. TisB is a membrane peptide that was shown to decrease proton motive force and ATP levels, consistent with its role in forming dormant cells. These results suggest that a DNA damage-induced toxin controls production of multidrug tolerant cells and thus provide a model of persister formation.
细菌会引发应激反应，使细胞免受 DNA 损伤剂等致死因素的伤害。细菌群体还会形成休眠细胞，即具有高度抗生素耐药性的休眠细胞，在生物膜感染的抗性中起着重要作用。应激反应和休眠似乎代表了细胞生存的两种替代策略。休眠细胞形成的机制尚不清楚，但分离出的休眠细胞表现出毒素/抗毒素（TA）转录本水平升高。我们之前发现，在暴露于 DNA 损伤抗生素后，SOS 反应的一个或多个成分会诱导休眠细胞的形成。SOS 反应在大肠杆菌中诱导几个 TA 基因的表达。在这里，我们表明 tisAB/istR 这一特定 SOS-TA 基因座的敲除会导致对环丙沙星（一种引起 DNA 损伤的抗生素）耐药的休眠细胞数量急剧减少。逐步给予环丙沙星会以 tisAB 依赖的方式诱导休眠细胞的形成，并且产生 TisB 毒素的细胞对多种抗生素具有耐药性。TisB 是一种膜肽，它被证明会降低质子动力势和 ATP 水平，这与其在形成休眠细胞中的作用一致。这些结果表明，一种由 DNA 损伤诱导的毒素控制着多药耐药细胞的产生，从而为休眠细胞形成提供了一种模型。
