Tolerance and persistence are superficially similar phenomena by which bacteria survive bactericidal antibiotics. It is assumed that the same physiology underlies survival of individual tolerant and persistent bacteria. However, by comparing tolerance and persistence during Salmonella Typhimurium infection, we reveal that these two phenomena are underpinned by different bacterial physiologies. Multidrug-tolerant mutant Salmonella enter a near-dormant state protected from immune-mediated genotoxic damages. However, the numerous tolerant cells, optimized for survival, lack the capabilities necessary to initiate infection relapse following antibiotic withdrawal. In contrast, persisters retain an active state. This leaves them vulnerable to accumulation of macrophage-induced dsDNA breaks but concurrently confers the versatility to initiate infection relapse if protected by RecA-mediated DNA repair. Accordingly, recurrent, invasive, non-typhoidal Salmonella clinical isolates display hallmarks of persistence rather than tolerance during antibiotic treatment. Our study highlights the complex trade-off that antibiotic-recalcitrant Salmonella balance to act as a reservoir for infection relapse.

耐受性和持久性是表面上相似的现象，细菌通过杀菌抗生素存活。假设相同的生理学是个体耐受性和持久性细菌生存的基础。然而，通过比较鼠伤寒沙门氏菌感染期间的耐受性和持久性，我们发现这两种现象是由不同的细菌生理学支撑的。耐多药突变沙门氏菌进入接近休眠状态，免受免疫介导的基因毒性损害。然而，为生存而优化的众多耐受细胞缺乏在抗生素停药后引发感染复发所必需的能力。相反，持久化器保持活动状态。这使它们容易受到巨噬细胞诱导的 dsDNA 断裂累积的影响，但如果受到 RecA 介导的 DNA 修复的保护，它们同时具有启动感染复发的多功能性。因此，复发性、侵袭性、非伤寒沙门氏菌临床分离株在抗生素治疗期间表现出持久性而非耐受性的特征。我们的研究强调了抗生素顽固性沙门氏菌平衡作为感染复发宿主的复杂权衡。