Proenca A M, Rang C U, Chao L
Immunology and Microbiology Laboratory, School of Health and Life Sciences, Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Institute of Biology, Freie Universität Berlin, Berlin, Germany.
Antimicrob Agents Chemother. 2025 Apr 2;69(4):e0131324. doi: 10.1128/aac.01313-24. Epub 2025 Feb 21.
Despite the various strategies that microorganisms have evolved to resist antibiotics, survival to drug treatments can be driven by subpopulations of susceptible bacteria in a transient state of dormancy. This phenotype, known as bacterial persistence, arises due to a natural and ubiquitous heterogeneity of growth states in bacterial populations. Nonetheless, the unifying mechanism of persistence remains unknown, with several pathways being able to trigger the phenotype. Here, we show that asymmetric damage partitioning, a form of cellular aging, produces the underlying phenotypic heterogeneity upon which persistence is triggered. Using single-cell microscopy and microfluidic devices, we demonstrate that deterministic asymmetry in exponential phase populations leads to a state of growth stability, which prevents the spontaneous formation of persisters. However, as populations approach stationary phase, aging bacteria-those inheriting more damage upon division-exhibit a sharper growth rate decline, increased probability of growth arrest, and higher persistence rates. These results indicate that persistence triggers are biased by bacterial asymmetry, thus acting upon the deterministic heterogeneity produced by cellular aging. This work suggests unifying mechanisms for persistence and offers new perspectives on the treatment of recalcitrant infections.
尽管微生物已经进化出各种策略来抵抗抗生素，但药物治疗后的存活可能由处于短暂休眠状态的敏感细菌亚群驱动。这种表型，即细菌持留性，是由于细菌群体中生长状态自然且普遍存在的异质性而产生的。然而，持留性的统一机制仍然未知，有几种途径能够触发这种表型。在这里，我们表明不对称损伤分配，一种细胞衰老形式，产生了触发持留性的潜在表型异质性。使用单细胞显微镜和微流控装置，我们证明指数期群体中的确定性不对称导致生长稳定状态，这阻止了持留菌的自发形成。然而，随着群体接近稳定期，衰老细菌——那些在分裂时继承更多损伤的细菌——表现出更急剧的生长速率下降、更高的生长停滞概率和更高的持留率。这些结果表明，持留性触发因素受细菌不对称性的影响，从而作用于细胞衰老产生的确定性异质性。这项工作提出了持留性的统一机制，并为难治性感染的治疗提供了新的视角。
