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Glycerol-Driven Energy and Proteostasis Underpin Antibiotic Tolerance in Escherichia coli

ABSTRACT: Bacterial persisters are frequently described as metabolically dormant, yet the endogenous metabolic programs that sustain survival during prolonged nutrient limitation remain poorly understood. Here, using stationary-phase Escherichia coli as a model of antibiotic tolerance, we combine proteomics, genetics, metabolic phenotyping, and single-cell imaging to define a metabolic framework underlying persistence. Perturbation of tricarboxylic acid cycle function broadly reprogrammed stationary-phase physiology, suppressing lipid and glycerol metabolism, altering energy homeostasis and proteostasis, and reducing antibiotic tolerance. Systems-level analyses identified phospholipid-derived glycerol catabolism as a central metabolic node linking endogenous carbon recycling to persistence. Genetic disruption of glycerol utilization impaired proton motive force homeostasis, reduced formation of large polar protein aggregates, altered division-associated remodeling, and sensitized cells to antibiotic-induced lysis. Functional metabolic assays further revealed that persisters retain a selective capacity to utilize glycerol for rapid proton motive force restoration without growth resumption. Together, our findings support a model in which stationary-phase persisters are not metabolically inert but sustained through endogenous metabolic rewiring that coordinates energy maintenance, proteostasis, and antibiotic tolerance.

INSTRUMENT(S):

ORGANISM(S): Escherichia Coli

TISSUE(S): Cell Culture

SUBMITTER: Han Ngo

LAB HEAD: Mehmet Orman

PROVIDER: PXD079272 | Pride | 2026-06-12

REPOSITORIES: Pride

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	atpA_1.xlsx	Xlsx
	atpA_2.xlsx	Xlsx
	atpA_3.xlsx	Xlsx
	checksum.txt	Txt
	crp_1.xlsx	Xlsx

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