# Elucidating the mechanisms of transient polymyxin resistance in pathogenic E. coli.

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2020 · $30,221

## Abstract

Defining Differences in how LPS modification is Regulated in Different E. coli pathotypes
Project Summary
Cells encounter a constant barrage of extracellular cues to which they respond using only the finite number of
signal transduction pathways encoded within their genome. While we understand how individual signal
transduction systems operate, little is known about how distinct signaling systems interact to integrate
information and/or expand their signal responses. The overall goal of this project is to understand how signaling
flexibility benefits the responses of different E. coli strains to cationic polypeptides. Although much attention is
placed on the acquisition of antibiotic resistance markers by the Enterobacteriaceae, there is increasing evidence
that bacteria can also mount transient resistance to antibiotics via the upregulation of chromosomally encoded
markers. For example, the pmrC gene encoded by Salmonella spp and E. coli species is an orthologue of the
mcr-1 gene that imparts resistance to colistin antibiotics. We have recently demonstrated that transient
resistance to polymyxin B arises in strains of uropathogenic E. coli, following stimulation with ferric iron. We
subsequently found that the transient polymyxin B resistance is brought about via the activation of the PmrB
sensor kinase, a member of the PmrAB two-component system (TCS). Bacterial TCSs comprise a membrane-
embedded histidine kinase that is the signal receptor, and a response regulator protein that directs the
corresponding cellular changes. Although there are sequence-based determinants that dictate specificity among
cognate TCS partners, we discovered strong interactions between the PmrAB and QseBC TCSs, in which the
PmrB histidine kinase readily activates both its cognate partner PmrA and the non-cognate response regulator
QseB in response to ferric iron, leading to a 16-fold increase in the MIC. I hypothesize that coordinated regulation
of PmrA and QseB leads to upregulation of genes critical for lipid A modification that in turn protects bacteria
from the insults of polymyxin B and other cationic polypeptides. I will test this hypothesis in three aims, in which
I will: (1) Define the PmrA and QseB regulons in response to polymyxin B and define the mechanism by which
PmrA and QseB activation leads to polymyxin B resistance. (2) Determine how the QseBC and PmrAB
interactions have evolved to benefit bacterial fitness in different niches, and; (3) Ascertain how the amount of
conservation present in the QseBC-PmrAB signaling cascade in E. coli strains from different phylogenetic clades
and with different pathogenic strategies. Towards these goals, an inter-disciplinary approach will be followed,
encompassing molecular biology, genome-wide analyses of transcription and robust murine models of infection.
Combined these studies will provide mechanistic details into a mechanism that allows bacteria to survive one of
the last resort antibiotics and will provide insight...

## Key facts

- **NIH application ID:** 9987258
- **Project number:** 5F31AI143244-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Melanie N Hurst
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,221
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987258

## Citation

> US National Institutes of Health, RePORTER application 9987258, Elucidating the mechanisms of transient polymyxin resistance in pathogenic E. coli. (5F31AI143244-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9987258. Licensed CC0.

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