Antibiotic persistence (heterotolerance) allows a sub-population of bacteria to survive antibiotic-induced killing and contributes to the evolution of antibiotic resistance. Although bacteria typically live in microbial communities with complex ecological interactions, little is known about how microbial ecology affects antibiotic persistence. Here, we demonstrated within a synthetic two-species microbial mutualism of Escherichia coli and Salmonella enterica that the combination of cross-feeding and community spatial structure can emergently cause high antibiotic persistence in bacteria by increasing the cell-to-cell heterogeneity. Tracking ampicillin-induced death for bacteria on agar surfaces, we found that E. coli forms up to 55 times more antibiotic persisters in the cross-feeding coculture than in monoculture. This high persistence could not be explained solely by the presence of S. enterica, the presence of cross-feeding, average nutrient starvation, or spontaneous resistant mutations. Time-series fluorescent microscopy revealed increased cell-to-cell variation in E. coli lag time in the mutualistic co-culture. Furthermore, we discovered that an E. coli cell can survive antibiotic killing if the nearby S. enterica cells on which it relies die first. In conclusion, we showed that the high antibiotic persistence phenotype can be an emergent phenomenon caused by a combination of cross-feeding and spatial structure. Our work highlights the importance of considering spatially structured interactions during antibiotic treatment and understanding microbial community resilience more broadly.

中文翻译：

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空间结构合成微生物互利共生中的新兴抗生素持久性

抗生素持久性（异耐受性）使细菌亚群能够在抗生素诱导的杀灭作用下存活下来，并有助于抗生素耐药性的进化。尽管细菌通常生活在具有复杂生态相互作用的微生物群落中，但人们对微生物生态如何影响抗生素持久性知之甚少。在这里，我们证明了在大肠杆菌和肠沙门氏菌的合成两种微生物的共生中，交叉喂养和群落空间结构的结合可以通过增加细胞间的异质性来突然导致细菌中抗生素的高持久性。通过追踪氨苄青霉素诱导的琼脂表面细菌死亡，我们发现，在交叉饲养共培养中，大肠杆菌形成的抗生素持久性比单一培养多 55 倍。这种高持久性不能仅仅用肠沙门氏菌的存在、交叉喂养、平均营养缺乏或自发耐药突变来解释。时间序列荧光显微镜显示，在互惠共培养中，大肠杆菌滞后时间的细胞间变异增加。此外，我们发现，如果大肠杆菌细胞所依赖的附近的肠沙门氏菌细胞首先死亡，那么它就可以在抗生素杀死后存活下来。总之，我们表明，高抗生素持久性表型可能是交叉喂养和空间结构相结合引起的一种新兴现象。我们的工作强调了在抗生素治疗期间考虑空间结构相互作用以及更广泛地了解微生物群落恢复力的重要性。