Single-cell microfluidics enabled dynamic evaluation of drug combinations on antibiotic resistance bacteria.
Single-cell microfluidics enabled dynamic evaluation of drug combinations on antibiotic resistance bacteria.
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DOI：
10.1016/j.talanta.2023.124814
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发表时间：
2023-06
期刊：
影响因子：
6.1
通讯作者：
Xiaobo Li;Yanqing Song;Xiuzhao Chen;Jianan Yin;P. Wang;He Huang;Huabing Yin
中科院分区：
文献类型：
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作者：
Xiaobo Li;Yanqing Song;Xiuzhao Chen;Jianan Yin;P. Wang;He Huang;Huabing Yin
抗生素耐药性的迅速蔓延已成为对全球健康的重大威胁，但新抗生素的开发速度却赶不上新耐药性的出现。为了治疗多重耐药细菌并延长现有抗生素的使用寿命，一种有效的策略是使用抗生素和/或佐剂的组合。然而，评估药物组合主要是基于终点棋盘测量，这为研究作用机制和临床结果的差异提供了有限的信息。本研究采用单细胞微流体技术在3小时内快速评价抗生素联合用药的疗效和作用方式。以多药耐药鲍曼不动杆菌为研究重点，评价盐酸小檗碱（BBH，作为佐剂）与碳青霉烯类（美罗培南，MEM）或β-内酰胺类抗生素联合用药。实时跟踪单个细胞到可编程递送的抗生素揭示了多种表型（即，易感，耐药和持久细胞）的保真度。我们的研究发现，BBH促进抗生素在细胞内的积累，表明协同作用（FICI = 0.5）。例如，256mg /L BBH和16mg /L MEM的组合杀灭效果与MEM的MIC （64mg /L）相似（即抑制率为90%）。重要的是，如果用任何一种药物预先对细菌施加压力，这种组合的协同效应就会减弱。这些信息对于理解联合治疗的潜在机制至关重要。总的来说，我们的平台提供了一种有前途的方法来评估细菌种群对抗生素的动态和异质性反应，这将促进新药的发现并减少新出现的抗生素耐药性。
The rapid spread of antibiotic resistance has become a significant threat to global health, yet the development of new antibiotics is outpaced by emerging new resistance. To treat multidrug-resistant bacteria and prolong the lifetime of existing antibiotics, a productive strategy is to use combinations of antibiotics and/or adjuvants. However, evaluating drug combinations is primarily based on end-point checkerboard measurements, which provide limited information to study the mechanism of action and the discrepancies in the clinical outcomes. Here, single-cell microfluidics is used for rapid evaluation of the efficacy and mode of action of antibiotic combinations within 3 h. Focusing on multidrug-resistantAcinetobacter baumannii,the combination between berberine hydrochloride (BBH, as an adjuvant) and carbapenems (meropenem, MEM) or β-lactam antibiotic is evaluated. Real-time tracking of individual cells to programmable delivered antibiotics reveals multiple phenotypes (i.e., susceptible, resistant, and persistent cells) with fidelity. Our study discovers that BBH facilitates the accumulation of antibiotics within cells, indicating synergistic effects (FICI = 0.5). For example, the combination of 256 mg/L BBH and 16 mg/L MEM has a similar killing effect (i.e., the inhibition rates >90%) as the MIC of MEM (64 mg/L). Importantly, the synergistic effect of a combination can diminish if the bacteria are pre-stressed with any single drug. Such information is vital for understanding the underlying mechanisms of combinational treatments. Overall, our platform provides a promising approach to evaluate the dynamic and heterogenous response of a bacterial population to antibiotics, which will facilitate new drug discovery and reduce emerging antibiotic resistance.