Metabolism-dependent succinylation governs resource allocation for antibiotic resistance

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Understanding how organisms allocate resources to maintain biological functions is crucial.
• Mobilized colistin resistance (mcr-1) provides a model to study resource reallocation for antibiotic resistance.
• Mcr-1 confers resistance by modifying lipopolysaccharide (LPS).

Purpose of the Study:

• To investigate the mechanisms by which bacteria reallocate resources to support mcr-1-mediated colistin resistance.
• To elucidate the role of metabolic pathways and posttranslational modifications in sustaining antibiotic resistance.

Main Methods:

• Utilized the mobilized colistin resistance (mcr-1) gene as a model system.
• Analyzed metabolic flux redirection from glycolysis, pyruvate cycle, and LPS biosynthesis.
• Investigated changes in glycerophospholipid metabolism and phosphatidylethanolamine production.
• Assessed the impact of resource reallocation on protein succinylation (e.g., TPI, CpxR, PdhR).
• Examined the effect of exogenous succinate and α-ketoglutarate on succinylation levels.

Main Results:

• Bacteria redirect metabolic resources from glycolysis and LPS biosynthesis towards glycerophospholipid metabolism to produce phosphatidylethanolamine.
• This reallocation reduces lipopolysaccharide (LPS) content, limiting colistin binding and conferring resistance.
• Succinyl-coenzyme A (CoA) levels are down-regulated, diminishing protein succinylation.
• Restoration of succinylation via exogenous succinate or α-ketoglutarate attenuates colistin resistance.
• Succinylation of specific proteins (TPI, CpxR, PdhR) impacts metabolic flux and LPS biosynthesis.

Conclusions:

• Bacteria employ a novel resource allocation strategy involving metabolism-driven posttranslational protein modification to sustain antibiotic resistance.
• This mechanism involves down-regulating succinylation to limit LPS modification and content, thereby enhancing resistance.
• Targeting these metabolic and posttranslational regulatory pathways could offer new strategies to combat antibiotic resistance.