A pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis

Tirthankar Mohanty, Christofer A. Q. Karlsson, Yashuan Chao, Erik Malmström, Eleni Bratanis, Andrietta Grentzmann, Martina Mørch, Victor Nizet, Lars Malmström, Adam Linder, Oonagh Shannon () and Johan Malmström ()
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Tirthankar Mohanty: Lund, Lund University
Christofer A. Q. Karlsson: Lund, Lund University
Yashuan Chao: Lund, Lund University
Erik Malmström: Lund, Lund University
Eleni Bratanis: Lund, Lund University
Andrietta Grentzmann: Lund, Lund University
Martina Mørch: Lund, Lund University
Victor Nizet: University of California, San Diego School of Medicine
Lars Malmström: Lund, Lund University
Adam Linder: Lund, Lund University
Oonagh Shannon: Lund, Lund University
Johan Malmström: Lund, Lund University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior reduction of the inflammatory response in kidneys and partial restoration of sepsis-induced metabolic dysfunction. Mem introduced sepsis-independent perturbations in the mitochondrial proteome that Gcc counteracted. We provide a strategy for the quantitative and organotypic assessment of treatment effects of candidate therapies in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.

Date: 2023
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DOI: 10.1038/s41467-023-39269-9

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