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This study reveals that Pseudomonas aeruginosa bacteria monitor their cell envelope synthesis through a metabolic checkpoint involving cyclic di-GMP signaling. Researchers found that antibiotics targeting early peptidoglycan biosynthesis steps cause accumulation of acetyl-CoA, a metabolite normally consumed during cell envelope production, which directly inhibits phosphodiesterase enzymes that break down c-di-GMP. This mechanism allows bacteria to sense disruptions in cell envelope biosynthesis and respond by promoting biofilm formation rather than maintaining motile growth.
Why it matters
Understanding how bacteria sense cell wall stress and switch to protective biofilm states could inform development of anti-biofilm therapies and more effective antibiotic strategies. The discovery that acetyl-CoA acts as a metabolic sensor may represent a conserved mechanism across bacterial species, offering potential broad-spectrum therapeutic targets.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
The bacterial second messenger cyclic dimeric guanosine monophosphate (c-di-GMP) drives the transition from motile to biofilm lifestyles, yet the mechanisms by which bacteria couple cell envelope stress to c-di-GMP signaling remain poorly understood. Here, we show that sub-inhibitory concentrations of antibiotics targeting early cytoplasmic steps of peptidoglycan (PG) biosynthesis, but not inhibitors of PG polymerization, membrane integrity, or other intracellular processes, specifically elevate intracellular c-di-GMP levels in Pseudomonas aeruginosa. Using live-cell imaging and in vitro enzymatic assays, we demonstrate that this elevation results from reduced phosphodiesterase (PDE) activity rather than increased diguanylate cyclase (DGC) activity, with multiple PDEs contributing to the response. A screen of the complete P. aeruginosa DGC/PDE mutant library identified DipA, BifA, RocR, and RmcA as the primary PDEs mediating this effect. Strikingly, we find that acetyl-CoA, a central metabolite consumed during cell envelope precursor biosynthesis, directly inhibits PDE activity by competing for the conserved EAL domain active site, as supported by biochemical assays with purified RocR and molecular docking analysis. Because EAL domain residues that contact acetyl-CoA are broadly conserved across bacterial species, this mechanism may represent a widespread strategy for sensing metabolic perturbations of cell envelope synthesis. Together, these findings reveal that P. aeruginosa monitors the metabolic status of cell envelope biogenesis through acetyl-CoA-mediated allosteric inhibition of c-di-GMP PDEs, linking envelope biosynthetic flux to adaptive biofilm formation.
Source: A metabolic checkpoint coordinates bacterial cell envelope biosynthesis and c-di-GMP signaling