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Global reprogramming of virulence and antibiotic resistance in Pseudomonas aeruginosa by a single nucleotide polymorphism in elongation factor, fusA1

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Maunders, Eve 
Triniman, Rory 
Western, Joshua 
Rahman, Taufiq 


Pseudomonas aeruginosa is a common opportunistic pathogen. The gene encoding an elongation factor, FusA1, is frequently mutated in clinical isolates of P. aeruginosa from patients with cystic fibrosis (CF). Recent work has shown that fusA1 mutants often display elevated aminoglycoside resistance due to increased expression of the efflux pump, MexXY. Here, we isolated a spontaneous gentamicin-resistant fusA1 mutant (FusA1P443L) in which mexXY expression was increased. Through a combination of proteomic and transcriptomic analyses, we found that the fusA1 mutant also exhibited large-scale but discrete changes in the expression of key pathogenicity-associated genes. Most notably, the fusA1 mutant displayed greatly increased expression of the Type III Secretion system (T3SS), widely considered to be the most potent virulence factor in the P. aeruginosa arsenal, and also elevated expression of the Type VI (T6) secretion machinery. This was unexpected because expression of the T3SS is usually reciprocally coordinated with T6 secretion system expression. The fusA1 mutant also displayed elevated exopolysaccharide production, dysregulated siderophore production, elevated ribosome synthesis, and transcriptomic signatures indicative of translational stress. Each of these phenotypes (and almost all of the transcriptomic and proteomic changes associated with the fusA1 mutation) were restored to levels comparable to that in the PAO1-derived progenitor strain by expression of the wild-type fusA1 gene in trans, indicating that the mutant gene is recessive. Our data show that in addition to elevating antibiotic resistance through mexXY expression (and also additional contributory resistance mechanisms), mutations in fusA1 can lead to highly-selective dysregulation of virulence gene expression.



FusA1, Pseudomonas aeruginosa, Pseudomonas aeruginosa (P. aeruginosa), Type III secretion, Type III secretion system (T3SS), Type VI secretion, Type VI secretion system, aminoglycoside, antibiotic resistance, exopolysaccharide, proteomics, transcriptomics, translation, Bacterial Proteins, Drug Resistance, Bacterial, Gene Expression Regulation, Bacterial, Mutation, Peptide Elongation Factor G, Polymorphism, Single Nucleotide, Pseudomonas aeruginosa, Type III Secretion Systems, Type VI Secretion Systems, Virulence Factors

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Journal of Biological Chemistry

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Evelyn Trust (17/51)
MRC (MR/K50127X/1)
Biotechnology and Biological Sciences Research Council (BB/M019411/1)
This work was supported by studentship MR/K50127X/1 (to EAM) from the MRC DTP programme, and by two flexible supplement awards (also from the MRC) for training in proteomic and transcriptomic analysis. RCT was supported by a PhD studentship from Hughes Hall Cambridge. Elements of the biochemical and genetic characterisation were supported by a grant from the Evelyn Trust.

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