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

Loading...
Thumbnail Image
Files
s41467-019-10271-4.pdf(895.29 KB)
Published Version
41467_2019_10271_MOESM1_ESM.pdf(956.35 KB)
Supplementary Information
41467_2019_10271_MOESM2_ESM.pdf(70.61 KB)
Reporting Summary
Date
2019-05-27
Authors
An, Shi-qi
Murtagh, Julie
Twomey, Kate B.
Gupta, Manoj K.
O'Sullivan, Timothy P.
Ingram, Rebecca
Valvano, Miguel A.
Tang, Ji-liang
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Nature Limited
Research Projects
Organizational Units
Journal Issue
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.
Description
Keywords
Structure prediction , Membrane-proteins , Sensor kinase , Bacterial , Virulence , Genes , Reconstitution , Tobramycin , Topology , Molecule
Citation
An, S.-q., Murtagh, J., Twomey, K. B., Gupta, M. K., O'Sullivan, T. P., Ingram, R., Valvano, M. A. and Tang, J. L. (2019) 'Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies signal analogues', Nature Communications, 10, 2334 (11pp). doi: 10.1038/s41467-019-10271-4
Link to publisher’s version