Loss of RND-Type Multidrug Efflux Pumps Triggers Iron Starvation and Lipid A Modifications in Pseudomonas aeruginosa.
Justyna W AdamiakVarsha JhawarVincent BonifayCourtney E ChandlerInga V LeusRobert K ErnstHerbert P SchweizerHelen I ZgurskayaPublished in: Antimicrobial agents and chemotherapy (2021)
Transporters belonging to the resistance-nodulation-division (RND) superfamily of proteins are invariably present in the genomes of Gram-negative bacteria and are largely responsible for the intrinsic antibiotic resistance of these organisms. The numbers of genes encoding RND transporters per genome vary from 1 to 16 and correlate with the environmental versatilities of bacterial species. Pseudomonas aeruginosa strain PAO1, a ubiquitous nosocomial pathogen, possesses 12 RND pumps, which are implicated in the development of clinical multidrug resistance and known to contribute to virulence, quorum sensing, and many other physiological functions. In this study, we analyzed how P. aeruginosa's physiology adapts to a lack of RND-mediated efflux activities. A combination of transcriptomics, metabolomics, genetic, and analytical approaches showed that the P. aeruginosa PΔ6 strain, lacking the six best-characterized RND pumps, activates a specific adaptation response that involves significant changes in the abundance and activities of several transport system, quorum sensing, iron acquisition, and lipid A modification pathways. Our results demonstrate that these cells accumulate large quantities of Pseudomonas quinolone signals (PQS), which triggers iron starvation and activation of siderophore biosynthesis and acquisition pathways. The accumulation of iron in turn activates lipid A modification and membrane protection pathways. A transcriptionally regulated RND pump, MuxABC-OpmB, contributes to these transformations by controlling the concentration of coumarins. Our results suggest that these changes reduce the permeability barrier of the outer membrane and are needed to protect the cell envelope of efflux-deficient P. aeruginosa.
Keyphrases
- pseudomonas aeruginosa
- biofilm formation
- cystic fibrosis
- acinetobacter baumannii
- genome wide
- single cell
- iron deficiency
- staphylococcus aureus
- escherichia coli
- fatty acid
- transcription factor
- candida albicans
- cell death
- oxidative stress
- dna methylation
- drug resistant
- antimicrobial resistance
- cell therapy
- gram negative
- endothelial cells
- mesenchymal stem cells
- cell cycle arrest
- methicillin resistant staphylococcus aureus
- genome wide identification
- cell proliferation
- signaling pathway
- human health
- sensitive detection
- life cycle
- pi k akt
- bone marrow