# Mechanisms of PbgA involvement in Salmonella Typhimurium lipid homeostasis for bacterial pathogenesis

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2022 · $360,700

## Abstract

PROJECT SUMMARY/ABSTRACT
 Salmonella enterica serovar Typhimurium (STm) cause bacteremia in immunocompromised humans by
surviving within the vacuoles of macrophages (MΦs). Treatment demands antibiotics that can penetrate to the
vacuolar salmonellae and fluoroquinolones are currently preferred. Consequently, resistant STm isolates have
emerged and new therapies are necessary. Like for most Gram-negative bacteria, Enterobacteriaceae produce
an outer-membrane (OM) lipid bilayer that forms a barrier to the environment and protects against antibiotic
killing and host-immune responses. STm regulate the glycerophospholipid (GPL) and the lipopolysaccharide
(LPS) molecules within their asymmetric surface bilayer to enhance the barrier and promote survival in MΦs
during bacteremia. However, the exact bacterial lipid-remodeling proteins and mechanisms necessary during
infection are largely unknown.
 We showed that STm rely upon a conserved enterobacterial transmembrane protein, PbgA, to maintain
OM-lipid homeostasis for barrier function and survival in MΦs during bacteremia in mice. PbgA binds
tetraacylated cardiolipin (CL)-GPL molecules and directs their trafficking to the OM in response to host cues.
The data support that STm adapted PbgA to promote LPS stability and OM homeostasis for survival within
host vacuoles. We hypothesize that salmonellae exploit structural features and binding interactions of
PbgA to control OM-lipid homeostasis during bacteremia. We will pursue this central inquiry by addressing
the following specific aims: 1) Define the functional contribution of PbgA-periplasmic domain (PD)
subregions and residues for OM-CL trafficking. 2) Define PbgA interactions within the STm envelope
necessary for lipid homeostasis and pathogenesis. 3) Delineate the role of PbgA and CL in STm-LPS
homeostasis during bacteremia.
 Minimal knowledge exists for how enteric bacteria transport GPL to the OM. To the best of our
knowledge, PbgA is one of the first examples of a protein involved in direct physical translocation of CL
molecules across the dual-membrane cell envelope of a Gram-negative bacterium. In understanding PbgA in
STm, we hope to inform common mechanisms of OM-lipid trafficking used by enteric pathogens to adapt and
survive within the mammalian host environment.

## Key facts

- **NIH application ID:** 10396459
- **Project number:** 5R01AI139248-05
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Zachary David Dalebroux
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $360,700
- **Award type:** 5
- **Project period:** 2018-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396459

## Citation

> US National Institutes of Health, RePORTER application 10396459, Mechanisms of PbgA involvement in Salmonella Typhimurium lipid homeostasis for bacterial pathogenesis (5R01AI139248-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10396459. Licensed CC0.

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