Molecular Biology, Cell Biology & Biochemistry Program, Boston University, Boston, Massachusetts; Biological Design Center, Boston University, Boston, Massachusetts.
Biological Design Center, Boston University, Boston, Massachusetts; Department of Biomedical Engineering, Boston University, Boston, Massachusetts.
Biophys J. 2019 Aug 6;117(3):563-571. doi: 10.1016/j.bpj.2019.07.005. Epub 2019 Jul 10.
Antibiotic resistance is generally associated with a fitness deficit resulting from the burden of producing and maintaining resistance machinery. This additional cost suggests that resistant bacteria will be outcompeted by susceptible bacteria in conditions without antibiotics. However, in practice, this process is slow in part because of regulation that minimizes expression of these genes in the absence of antibiotics. This suggests that if it were possible to turn on their expression, the cost would increase, thereby accelerating removal of resistant strains. Experimental and theoretical studies have shown that environmental chemicals can change the fitness cost associated with resistance and therefore have a significant impact on population dynamics. The multiple antibiotic resistance activator (MarA) is a clinically important regulator in Escherichia coli that activates downstream genes to increase resistance against multiple classes of antibiotics. Salicylate is an inducer of MarA that can be found in the environment and derepresses marA's expression. In this study, we sought to unravel the interplay between salicylate and the fitness cost of MarA-mediated antibiotic resistance. Using salicylate as an inducer of MarA, we found that a wide spectrum of concentrations can increase burden in resistant strains compared to susceptible strains. Induction resulted in rapid exclusion of resistant bacteria from mixed populations of antibiotic-resistant and susceptible cells. A mathematical model captures the process and predicts its effect in various environmental conditions. Our work provides a quantitative understanding of salicylate exposure on the fitness of different MarA variants and suggests that salicylate can lead to selection against MarA-mediated resistant strains. More generally, our findings show that natural inducers may serve to bias population membership and could impact antibiotic resistance and other important phenotypes.
抗生素耐药性通常与产生和维持耐药机制的负担导致的适应性缺陷有关。这种额外的成本表明，在没有抗生素的情况下，耐药细菌将被敏感细菌所淘汰。然而，在实践中，这个过程是缓慢的，部分原因是由于调节机制，使这些基因在没有抗生素的情况下最小化表达。这表明，如果能够启动它们的表达，成本将会增加，从而加速耐药菌株的清除。实验和理论研究表明，环境化学物质可以改变与耐药性相关的适应性成本，因此对种群动态有重大影响。多重抗生素耐药激活剂（MarA）是大肠杆菌中一种临床重要的调节剂，它激活下游基因，增加对多种抗生素的耐药性。水杨酸是 MarA 的诱导剂，可以在环境中找到，它可以解除 marA 的表达抑制。在这项研究中，我们试图揭示水杨酸与 MarA 介导的抗生素耐药性的适应性成本之间的相互作用。我们使用水杨酸作为 MarA 的诱导剂，发现与敏感菌株相比，广泛的浓度范围可以增加耐药菌株的负担。诱导导致耐药细菌在抗生素耐药和敏感细胞的混合种群中迅速被淘汰。一个数学模型捕捉了这个过程，并预测了它在各种环境条件下的效果。我们的工作提供了对水杨酸暴露对不同 MarA 变体适应性的定量理解，并表明水杨酸可能导致对 MarA 介导的耐药菌株的选择。更普遍地说，我们的发现表明，天然诱导剂可能有助于影响种群成员组成，并可能影响抗生素耐药性和其他重要表型。
