The University of Southampton
University of Southampton Institutional Repository

Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analogues

Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analogues
Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analogues

Pseudomonas aeruginosa, a significant opportunistic pathogen, can participate in inter-species communication through signaling by cis-2-unsaturated fatty acids of the diffusible signal factor (DSF) family. Sensing these signals leads to altered biofilm formation and increased tolerance to various antibiotics, and requires the histidine kinase PA1396. Here, we show that the membrane-associated sensory input domain of PA1396 has five transmembrane helices, two of which are required for DSF sensing. DSF binding is associated with enhanced auto-phosphorylation of PA1396 incorporated into liposomes. Further, we examined the ability of synthetic DSF analogues to modulate or inhibit PA1396 activity. Several of these analogues block the ability of DSF to trigger auto-phosphorylation and gene expression, whereas others act as inverse agonists reducing biofilm formation and antibiotic tolerance, both in vitro and in murine infection models. These analogues may thus represent lead compounds to develop novel adjuvants improving the efficacy of existing antibiotics.

2041-1723
1-11
An, Shi qi
0e05f480-cec1-4c0e-bc1d-359d30ea9a6e
Murtagh, Julie
915cf794-3035-413e-bfea-0bf375da2489
Twomey, Kate B.
66d5fee3-2daf-4e66-ac8e-61ee0b49bd11
Gupta, Manoj K.
99eb1d7c-b6e3-4f85-93c2-3d7fef9f6191
O’Sullivan, Timothy P.
c90626a5-3f55-45af-9887-590dea28c06d
Ingram, Rebecca
635fb207-e9a7-431b-b08a-befcad01d1a4
Valvano, Miguel A.
860ad4ea-4e77-4265-a035-feafa60725f8
Tang, Ji liang
74e46e1a-4f75-4c94-871d-317339f309f2
An, Shi qi
0e05f480-cec1-4c0e-bc1d-359d30ea9a6e
Murtagh, Julie
915cf794-3035-413e-bfea-0bf375da2489
Twomey, Kate B.
66d5fee3-2daf-4e66-ac8e-61ee0b49bd11
Gupta, Manoj K.
99eb1d7c-b6e3-4f85-93c2-3d7fef9f6191
O’Sullivan, Timothy P.
c90626a5-3f55-45af-9887-590dea28c06d
Ingram, Rebecca
635fb207-e9a7-431b-b08a-befcad01d1a4
Valvano, Miguel A.
860ad4ea-4e77-4265-a035-feafa60725f8
Tang, Ji liang
74e46e1a-4f75-4c94-871d-317339f309f2

An, Shi qi, Murtagh, Julie, Twomey, Kate B., Gupta, Manoj K., O’Sullivan, Timothy P., Ingram, Rebecca, Valvano, Miguel A. and Tang, Ji liang (2019) Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analogues. Nature Communications, 10 (1), 1-11, [2334]. (doi:10.1038/s41467-019-10271-4).

Record type: Article

Abstract

Pseudomonas aeruginosa, a significant opportunistic pathogen, can participate in inter-species communication through signaling by cis-2-unsaturated fatty acids of the diffusible signal factor (DSF) family. Sensing these signals leads to altered biofilm formation and increased tolerance to various antibiotics, and requires the histidine kinase PA1396. Here, we show that the membrane-associated sensory input domain of PA1396 has five transmembrane helices, two of which are required for DSF sensing. DSF binding is associated with enhanced auto-phosphorylation of PA1396 incorporated into liposomes. Further, we examined the ability of synthetic DSF analogues to modulate or inhibit PA1396 activity. Several of these analogues block the ability of DSF to trigger auto-phosphorylation and gene expression, whereas others act as inverse agonists reducing biofilm formation and antibiotic tolerance, both in vitro and in murine infection models. These analogues may thus represent lead compounds to develop novel adjuvants improving the efficacy of existing antibiotics.

Text
s41467-019-10271-4 - Version of Record
Available under License Creative Commons Attribution.
Download (916kB)

More information

Accepted/In Press date: 24 April 2019
Published date: 27 May 2019

Identifiers

Local EPrints ID: 431711
URI: http://eprints.soton.ac.uk/id/eprint/431711
ISSN: 2041-1723
PURE UUID: 76902592-e12e-477e-aaa2-8bd11e2646bc

Catalogue record

Date deposited: 14 Jun 2019 16:30
Last modified: 07 Oct 2020 00:53

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×