Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02114, USA.
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA; Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
Cell Chem Biol. 2022 Feb 17;29(2):276-286.e4. doi: 10.1016/j.chembiol.2021.12.010. Epub 2022 Jan 5.
β-Lactam antibiotics disrupt the assembly of peptidoglycan (PG) within the bacterial cell wall by inhibiting the enzymatic activity of penicillin-binding proteins (PBPs). It was recently shown that β-lactam treatment initializes a futile cycle of PG synthesis and degradation, highlighting major gaps in our understanding of the lethal effects of PBP inhibition by β-lactam antibiotics. Here, we assess the downstream metabolic consequences of treatment of Escherichia coli with the β-lactam mecillinam and show that lethality from PBP2 inhibition is a specific consequence of toxic metabolic shifts induced by energy demand from multiple catabolic and anabolic processes, including accelerated protein synthesis downstream of PG futile cycling. Resource allocation into these processes is coincident with alterations in ATP synthesis and utilization, as well as a broadly dysregulated cellular redox environment. These results indicate that the disruption of normal anabolic-catabolic homeostasis by PBP inhibition is an essential factor for β-lactam antibiotic lethality.
β-内酰胺类抗生素通过抑制青霉素结合蛋白（PBPs）的酶活性来破坏细菌细胞壁中肽聚糖（PG）的组装。最近的研究表明，β-内酰胺类药物治疗会引发 PG 合成和降解的无效循环，这突显了我们对β-内酰胺类抗生素抑制 PBPs 的致死作用的理解存在重大差距。在这里，我们评估了用β-内酰胺类药物美西林治疗大肠杆菌的下游代谢后果，并表明 PBP2 抑制的致死性是由能量需求引起的多种分解代谢和合成代谢过程引起的有毒代谢转变的特定后果，包括 PG 无效循环下游的加速蛋白合成。资源分配到这些过程与 ATP 合成和利用的改变以及广泛失调的细胞氧化还原环境同时发生。这些结果表明，PBP 抑制对正常合成代谢-分解代谢平衡的破坏是β-内酰胺类抗生素致死性的一个重要因素。
