Antibiotic-resistant ribosome variants arise spontaneously in bacterial populations; however, their impact on the overall bacterial physiology remains unclear. We studied the naturally arising antibiotic-resistant L22* ribosome variant of Bacillus subtilis and identified a Mg 2+ -dependent physiological cost. Coculture competition experiments show that Mg 2+ limitation hinders the growth of the L22* variant more than the wild type (WT), even under antibiotic pressure. This growth disadvantage of L22* cells is not due to lower ribosome abundance but rather due to reduced intracellular Mg 2+ levels. Coarse-grained elastic-network modeling of ribosome conformational dynamics suggests that L22* ribosomes associate more tightly with Mg 2+ when compared to WT. We combined the structural modeling and experimental measurements in a steady-state model to predict cellular adenosine 5′-triphosphate (ATP) levels, which also depend on Mg 2+ . Experiments confirmed a predicted ATP drop in L22* cells under Mg 2+ limitation, while WT cells were less affected. Intracellular competition for a finite Mg 2+ pool can thus suppress the establishment of an antibiotic-resistant ribosome variant.

中文翻译：

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抗生素耐药性的生理成本：来自细菌核糖体变体的见解


抗生素耐药核糖体变体在细菌种群中自发出现;然而，它们对整体细菌生理学的影响仍不清楚。我们研究了枯草芽孢杆菌天然产生的抗生素耐药性 L22* 核糖体变体，并确定了 Mg 2+ 依赖性的生理成本。共培养竞争实验表明，即使在抗生素压力下，Mg 2+ 限制也比野生型 （WT） 更能阻碍 L22 * 变体的生长。L22* 细胞的这种生长劣势不是由于核糖体丰度较低，而是由于细胞内 Mg 2+ 水平降低。核糖体构象动力学的粗粒度弹性网络模型表明，与 WT 相比，L22* 核糖体与 Mg 2+ 的结合更紧密。我们将结构建模和实验测量结合在稳态模型中，以预测细胞腺苷 5′-三磷酸 （ATP） 水平，该水平也取决于 Mg 2+。实验证实，在 Mg 2+ 限制下，L22* 细胞中预测的 ATP 下降，而 WT 细胞受到的影响较小。因此，对有限 Mg 2+ 库的细胞内竞争可以抑制抗生素耐药核糖体变体的建立。