RelA-mediated (p)ppGpp accumulation links glucose starvation to peptidoglycan synthesis arrest and spherical morphogenesis via PBP2x and FtsX in Streptococcus suis.

Authors

Tingting Jiang, Hongyu Wu, Ying Sun, Hengfei Yan, Minghui Ni, Shaohui Li, Menglei Liang, Lelin Zhao, Ziqian Xu, Shuaiyang Wang, Liangsheng Zhang, Lu Li, Rui Zhou, Qi Huang

Published in

Journal of bacteriology. Pages e0003026. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

Carbon starvation links nutrient sensing to bacterial morphogenesis, but the molecular pathway connecting glucose limitation to division failure remains unclear. In Streptococcus suis SC19, glucose limitation elevated RelA abundance and intracellular (p)ppGpp levels, slowed bacterial growth, and induced a reproducible spherical morphotype associated with selective impairment of peptidoglycan insertion. Inducible and constitutive RelA expression recapitulated the starvation phenotypes and (p)ppGpp accumulation in a dose- and time-dependent manner. The spherical morphotype resulting from glucose starvation-induced RelA activation and consequent (p)ppGpp accumulation coincided with decreased pbp2x and ftsX transcript levels, whereas pbp2b, ftsW, divIVA, ftsE, pcsB, and mltG displayed divergent expression patterns between starvation and RelA-induction conditions, findings that are consistent with pbp2x and ftsX acting as principal downstream effectors of the starvation-induced morphotype. Deletion of ftsX produced the rounded phenotype, and subinhibitory cefotaxime treatment targeting PBP2x induced progressive rounding; these manipulations together provide functional evidence that FtsX and PBP2x could contribute to (p)ppGpp-dependent PG arrest and spherical morphogenesis. Cross-species validation in S. pneumoniae and E. coli upon RelA induction produced comparable morphological and transcriptional changes. These results suggest that RelA-mediated (p)ppGpp accumulation couples glucose starvation to PG arrest and spherical morphogenesis via pbp2x and ftsX, nominating the (p)ppGpp-mediated stringent response as a regulatory hub for peptidoglycan biogenesis during cell division.IMPORTANCEBacterial survival depends on adapting morphogenesis to nutrient availability, yet the molecular links between carbon starvation and cell division remain poorly defined. In the zoonotic pathogen Streptococcus suis, glucose limitation triggers RelA-mediated accumulation of the alarmone (p)ppGpp, which arrests peptidoglycan synthesis and induces the morphological transition from ovoid to spherical cells. The downregulation of the key division components PBP2x and FtsX is likely an important driver of this morphological transition. Furthermore, this (p)ppGpp-dependent division "brake" is conserved in Streptococcus pneumoniae and Escherichia coli. By identifying a direct pathway coupling metabolic status to the division machinery, this work provides fundamental insights into how bacteria preserve cellular integrity under stress, highlighting potential targets for disrupting bacterial persistence and adaptation during infection.

PMID:
42446997
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.

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