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<p>Peptidoglycan (PG) is the primary structural component of the bacterial cell wall. However, many bacteria can switch into a wall-deficient “L-form” state, whereby they grow without PG synthesis and become completely resistant to cell-wall-targeting antibiotics. Teichoic acids (TAs) are major glycopolymers of Gram-positive bacteria that are attached to either the PG wall (WTA) or the lipid membrane (LTA). We show that L-form growth does not require either WTA or LTA. However, it does require the TagO protein, which initiates the synthesis of WTA. Inhibiting TagO with the antibiotic tunicamycin triggers a metabolic shift resulting in oxidative damage-mediated cell death, and this is highly synergistic with perturbations of the PG synthetic system. UDP-GlcNAc, a key precursor for both PG and TA synthesis, controls a metabolic switch leading either to balanced growth or oxidative damage. Our results demonstrate the pivotal role of UDP-GlcNAc in the mechanism of killing by cell wall inhibition.</p>

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Synergistic action of peptidoglycan and teichoic acid synthesis inhibitors leads to cell death by oxidative damage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月30日

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  • Yoshikazu Kawai,
  • Yousef Dashti,
  • Jeff Errington

摘要

Peptidoglycan (PG) is the primary structural component of the bacterial cell wall. However, many bacteria can switch into a wall-deficient “L-form” state, whereby they grow without PG synthesis and become completely resistant to cell-wall-targeting antibiotics. Teichoic acids (TAs) are major glycopolymers of Gram-positive bacteria that are attached to either the PG wall (WTA) or the lipid membrane (LTA). We show that L-form growth does not require either WTA or LTA. However, it does require the TagO protein, which initiates the synthesis of WTA. Inhibiting TagO with the antibiotic tunicamycin triggers a metabolic shift resulting in oxidative damage-mediated cell death, and this is highly synergistic with perturbations of the PG synthetic system. UDP-GlcNAc, a key precursor for both PG and TA synthesis, controls a metabolic switch leading either to balanced growth or oxidative damage. Our results demonstrate the pivotal role of UDP-GlcNAc in the mechanism of killing by cell wall inhibition.