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The master virulence regulator PhoP dictates carbon metabolism by controlling cyclic AMP synthesis in Salmonella

Nick D Pokorzynski1, Elisabeth C Sams-Dodd1, Christopher Esneault1

  • 1Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, Connecticut, United States of America.

Plos Biology
|December 18, 2025
PubMed

Insights

Salmonella Typhimurium uses the PhoP regulator to maintain cyclic adenosine monophosphate (cAMP) levels during magnesium starvation. This allows the pathogen to utilize carbon sources effectively within host macrophages.

Area of Science:

  • Microbiology
  • Bacterial Pathogenesis
  • Metabolic Regulation

Background:

  • Salmonella Typhimurium encounters magnesium (Mg2+) starvation within macrophages, impacting its carbon metabolism.
  • Cytoplasmic Mg2+ starvation reduces cyclic adenosine monophosphate (cAMP), inhibiting the cAMP receptor protein (CRP) which controls carbon utilization.

Purpose of the Study:

  • To investigate how Salmonella Typhimurium utilizes CRP-cAMP-dependent carbon sources under low Mg2+ conditions.
  • To elucidate the role of the PhoP regulator in controlling CRP-cAMP activity and carbon metabolism during intracellular infection.

Main Methods:

  • Investigated the role of PhoP and its effectors (MgtA, MgtB, MgtC) in regulating CRP-cAMP activity.
  • Assessed the impact of Mg2+ import and ATP levels on adenylate cyclase (CyaA) activity.
  • Utilized genetic manipulation (mgtA mgtB mutant, crp* allele) and cAMP supplementation to restore CRP activity.

Main Results:

  • PhoP controls CRP-cAMP-dependent transcription, metabolism, and growth during Mg2+ starvation.
  • PhoP-activated MgtA and MgtB import Mg2+, essential for CyaA activity.
  • PhoP-activated MgtC maintains cAMP levels by preventing ATP-mediated inhibition of CyaA.

Conclusions:

  • PhoP reprograms Salmonella Typhimurium's metabolism by controlling cAMP synthesis and thus CRP activity under low Mg2+ conditions.
  • This mechanism allows Salmonella to adapt and utilize specific carbon sources within the macrophage environment.

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