Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality,Cell Chemical Biology

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Increased energy demand from anabolic-catabolic processes drives β-lactam antibiotic lethality
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2022-01-05 , DOI: 10.1016/j.chembiol.2021.12.010
Michael A Lobritz ₁ , Ian W Andrews ₂ , Dana Braff ₃ , Caroline B M Porter ₄ , Arnaud Gutierrez ₄ , Yoshikazu Furuta ₅ , Louis B G Cortes ₆ , Thomas Ferrante ₇ , Sarah C Bening ₄ , Felix Wong ₄ , Charley Gruber ₈ , Christopher W Bakerlee ₄ , Guillaume Lambert ₆ , Graham C Walker ₈ , Daniel J Dwyer ₉ , James J Collins ₁₀

Affiliation

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.
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; Department of Biomedical Engineering, Boston University, Boston, MA 02215, 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.
Institute for Medical Engineering & Science, Department of Biological Engineering, and Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
School of Applied and Engineering Physics, Cornell University, Ithaca, NY 14853, USA.
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Cell Biology and Molecular Genetics, Institute for Physical Science and Technology, Department of Biomedical Engineering, and Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, 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; Harvard-MIT Program in Health Sciences and Technology, Cambridge, MA 02139, USA.

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.

中文翻译：

合成代谢-分解代谢过程增加的能量需求推动了 β-内酰胺抗生素的致死率

β-内酰胺类抗生素通过抑制青霉素结合蛋白 (PBP) 的酶活性来破坏细菌细胞壁内肽聚糖 (PG) 的组装。最近表明，β-内酰胺处理启动了 PG 合成和降解的无效循环，突出了我们对 β-内酰胺抗生素抑制 PBP 的致死作用的理解的主要差距。在这里，我们评估了大肠杆菌治疗的下游代谢后果与β-内酰胺美西林并表明PBP2抑制的致死性是由多种分解代谢和合成代谢过程的能量需求引起的毒性代谢转变的特定结果，包括PG徒劳循环下游的加速蛋白质合成。这些过程中的资源分配与 ATP 合成和利用的改变以及广泛失调的细胞氧化还原环境是一致的。这些结果表明，PBP 抑制对正常合成代谢-分解代谢稳态的破坏是 β-内酰胺抗生素致死性的一个重要因素。

更新日期：2022-01-05

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