Nutrient Gradients Mediate Complex Colony-Level Antibiotic Responses in Structured Microbial Populations.
Nutrient Gradients Mediate Complex Colony-Level Antibiotic Responses in Structured Microbial Populations.
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DOI：
10.3389/fmicb.2022.740259
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发表时间：
2022
影响因子：
5.2
通讯作者：
Schultz, Daniel
中科院分区：
文献类型：
--
作者：
Stevanovic, Mirjana;Boukeke-Lesplulier, Thomas;Hupe, Lukas;Hasty, Jeff;Bittihn, Philip;Schultz, Daniel
由于单个细胞对药物的反应存在异质性，抗生素治疗往往不能消除细菌群。在生物膜等结构化细菌群体中，细菌代谢和环境运输过程导致突发性表型结构和向菌落内部自生的营养梯度，从而影响细胞生长、基因表达和对药物的易感性。即使在单个细胞中，存活也取决于药物作用和抗性基因表达之间的动态相互作用。在这种时空环境耦合的存在下，抗性的表达如何在种群间协调仍然是难以捉摸的。利用定制的微流控装置，我们观察了四环素耐药大肠杆菌的空间扩展微菌落对精确定义的动态药物方案的反应。我们发现药物诱导的细胞生长变化和抗性基因的生长依赖性表达之间存在复杂的相互作用，导致代谢物的重新分配和生长模式的重组。这种动态环境反馈对整个菌落的耐药调节产生不同的影响，产生动态表型结构，在暴露于高浓度药物时维持菌落生长，并增加种群水平对后续暴露的耐药性。一个连接代谢和基因表达调控的数学模型能够捕捉时空集落动力学的主要特征。揭示在空间扩展的种群中控制抗生素耐药性集体机制的基本原则将允许设计最佳药物方案来抵消它们。
Antibiotic treatments often fail to eliminate bacterial populations due to heterogeneity in how individual cells respond to the drug. In structured bacterial populations such as biofilms, bacterial metabolism and environmental transport processes lead to an emergent phenotypic structure and self-generated nutrient gradients toward the interior of the colony, which can affect cell growth, gene expression and susceptibility to the drug. Even in single cells, survival depends on a dynamic interplay between the drug’s action and the expression of resistance genes. How expression of resistance is coordinated across populations in the presence of such spatiotemporal environmental coupling remains elusive. Using a custom microfluidic device, we observe the response of spatially extended microcolonies of tetracycline-resistant E. coli to precisely defined dynamic drug regimens. We find an intricate interplay between drug-induced changes in cell growth and growth-dependent expression of resistance genes, resulting in the redistribution of metabolites and the reorganization of growth patterns. This dynamic environmental feedback affects the regulation of drug resistance differently across the colony, generating dynamic phenotypic structures that maintain colony growth during exposure to high drug concentrations and increase population-level resistance to subsequent exposures. A mathematical model linking metabolism and the regulation of gene expression is able to capture the main features of spatiotemporal colony dynamics. Uncovering the fundamental principles that govern collective mechanisms of antibiotic resistance in spatially extended populations will allow the design of optimal drug regimens to counteract them.
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DOI：
10.1016/j.bbapap.2008.11.005
发表时间：
2009-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Delcour AH
通讯作者：
Delcour AH
集体空间感应在工程细菌中协调图案缩放。
影响因子：
64.5
作者：
Cao Y;Ryser MD;Payne S;Li B;Rao CV;You L
通讯作者：
You L
细菌群落抗菌素耐药性的生态学和进化。
DOI：
10.1038/s41396-020-00832-7
发表时间：
2021-04
期刊：
The ISME journal
影响因子：
--
作者：
Bottery MJ;Pitchford JW;Friman VP
通讯作者：
Friman VP
DOI：
10.1073/pnas.2003700117
发表时间：
2020-09-08
影响因子：
11.1
作者：
Kowalski, Caitlin H.;Morelli, Kaesi A.;Cramer, Robert A.
通讯作者：
Cramer, Robert A.
影响因子：
16.6
作者：
Housden NG;Webby MN;Lowe ED;El-Baba TJ;Kaminska R;Redfield C;Robinson CV;Kleanthous C
通讯作者：
Kleanthous C