瑞士巴塞尔大学Dirk Bumann团队近期取得重要工作进展，他们研究提出，沙门氏菌的耐受和持久性对抗生素清除效果影响有限。相关研究成果2025年2月5日在线发表于《自然》杂志上。

据介绍，抗菌化合物对于控制细菌感染至关重要。在实验室条件下，应激诱导的细菌耐受性和持久性可能会削弱抗菌活性，但它们在生理条件下的定量影响尚不清楚。

研究人员通过感染小鼠和模拟组织环境的恒化器，确定了抗菌药物清除沙门氏菌的限制因素。抗生素恩诺沙星和头孢曲松在这两种条件下均表现出较差的抗沙门氏菌活性，主要原因是严重的营养匮乏限制了沙门氏菌的复制。其他与感染相关的条件，如酸性pH、葡萄糖、氧化应激、亚硝化应激、抗菌肽、渗透压、氧气限制、二氧化碳和碳酸盐，以及药物外排、毒素-抗毒素模块和细胞大小，影响有限。

基于沙门氏菌菌落形成单位（CFU）的双相下降，一部分具有高耐受性的沙门氏菌被认为是恩诺沙星清除的主要障碍。然而，这些数据具有误导性，因为菌落形成受到暴露后大量细菌被杀死的影响。更精确的单细胞实时检测显示，损伤过程均匀且缓慢，表明整个沙门氏菌群体均具有高耐受性。由此导致的大量细菌存活，最小化了超耐受性持久菌的影响。

因此，饥饿诱导的沙门氏菌整体耐受性是抗生素清除效果差的主要原因。这些发现强调了在生理条件下通过实时单细胞检测量化抗生素活性的重要性。

附：英文原文

Title: Limited impact of Salmonella stress and persisters on antibiotic clearance

Author: Fanous, Joseph, Claudi, Beatrice, Tripathi, Vishwachi, Li, Jiagui, Goormaghtigh, Frdric, Bumann, Dirk

Issue&Volume: 2025-02-05

Abstract: Antimicrobial compounds are essential for controlling bacterial infections. Stress-induced bacterial tolerance and persisters can undermine antimicrobial activities under laboratory conditions, but their quantitative effects under physiological conditions remain unclear1,2. Here we determined constraints on clearance of Salmonella by antimicrobials in infected mice and tissue-mimicking chemostats. The antibiotics enrofloxacin and ceftriaxone exhibited poor anti-Salmonella activity under both conditions, primarily owing to severe nutrient starvation, which restricted Salmonella replication3,4,5. Other infection-associated conditions, such as acidic pH, glucose, oxidative stress, nitrosative stress, antimicrobial peptides, osmolarity, oxygen limitation, carbon dioxide and carbonate, as well as drug efflux, toxin–antitoxin modules and cell size had limited effects. A subset of resilient Salmonella appeared as a key obstacle for clearance by enrofloxacin, based on the biphasic decline of Salmonella colony-forming units. However, these data were misleading, because colony formation was confounded by extensive post-exposure killing. More accurate single-cell, real-time assays showed uniformly slow damage, indicating high resilience across the entire Salmonella population. The resulting extensive survival of bulk bacteria minimized the effect of hyper-resilient persisters. Thus, starvation-induced general resilience of Salmonella was the main cause of poor antibiotic clearance. These findings highlight the importance of quantifying antibiotic activity with real-time, single-cell assays under physiological conditions.

DOI: 10.1038/s41586-024-08506-6

Source: https://www.nature.com/articles/s41586-024-08506-6