Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, San Diego, CA 92093, USA.
Department of Physics and Center for Biological Physics, Arizona State University, Tempe, AZ 85287-1504, USA.
Sci Adv. 2024 Nov 15;10(46):eadq5249. doi: 10.1126/sciadv.adq5249.
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 and identified a Mg-dependent physiological cost. Coculture competition experiments show that Mg 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 levels. Coarse-grained elastic-network modeling of ribosome conformational dynamics suggests that L22* ribosomes associate more tightly with Mg 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. Experiments confirmed a predicted ATP drop in L22* cells under Mg limitation, while WT cells were less affected. Intracellular competition for a finite Mg pool can thus suppress the establishment of an antibiotic-resistant ribosome variant.
耐药核糖体变异体在细菌群体中自发出现；然而，它们对整体细菌生理学的影响尚不清楚。我们研究了 中自然出现的抗生素耐药 L22核糖体变异体，并确定了一个依赖镁的生理代价。共培养竞争实验表明，即使在抗生素压力下，镁限制也会比野生型（WT）更严重地阻碍 L22变异体的生长。L22细胞的这种生长劣势不是由于核糖体丰度较低，而是由于细胞内镁水平降低。核糖体构象动力学的粗粒度弹性网络建模表明，与 WT 相比，L22核糖体与镁的结合更为紧密。我们将结构建模和实验测量结合在一个稳态模型中，以预测细胞腺苷 5'-三磷酸（ATP）水平，这也依赖于镁。实验证实了镁限制下 L22*细胞中预测的 ATP 下降，而 WT 细胞受影响较小。因此，对有限镁池的细胞内竞争可以抑制抗生素耐药核糖体变异体的建立。
