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Evaluating the Link between Efflux Pump Expression and Motility Phenotypes in Pseudomonas aeruginosa Treated with
Hannah K Lembke1, Kelsie M Nauta1, Ryan C Hunter2
1Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States of America.
Abstract:
Antibiotic resistance continues to rise as a global health threat. Novel antivirulence strategies diminish the drive for evolutionary pressure but still hinder a pathogen's ability to infect a host. Treatment of the highly virulent Pseudomonas aeruginosa strain PA14 with virulence inhibitors (R-2 and R-6) elicited widely varying transcriptional profiles. Of interest, the expression of a family of resistance-nodulation-division (RND) efflux pumps implicated in the intrinsic drug resistance of P. aeruginosa was significantly altered by R-2 and R-6 treatment. While structurally similar, these inhibitors caused differential expression of various RND efflux pumps within the Mex family─the R-2 treatment stimulated the expression of mexEF-oprN, while the R-6 treatment led to increased mexAB-oprM expression. Further expansion into a small library of virulence inhibitors revealed chemical motifs that trigger increases in the level of RND efflux pump expression. Additionally, activation of these efflux pumps suggests a low accumulation of virulence inhibitors in WT PA14. Treatment of an efflux pump-deficient strain with R-2 or R-6 resulted in inhibition of several virulence factors; for example, R-2 was found to abolish swimming motility. Collectively, treatment with either R-2 or R-6 gives rise to a convoluted transcriptomic response confounded by the impact of efflux pump expression on the system. However, understanding the moieties that lead to high expression of the efflux pumps enables the further rational design of novel virulence inhibitors that do not cause RND efflux pump activation.
Insights
Novel antivirulence drugs targeting Pseudomonas aeruginosa show promise but activate resistance mechanisms. Understanding these efflux pumps is key to designing better drugs that avoid resistance. This research explores drug-induced changes in bacterial defense systems.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Discovery
Background:
- Antibiotic resistance is a growing global health crisis.
- Antivirulence strategies offer an alternative to traditional antibiotics by disarming pathogens without killing them.
- Pseudomonas aeruginosa is a highly virulent bacterium known for its intrinsic drug resistance.
Purpose of the Study:
- To investigate the effects of novel antivirulence compounds (R-2 and R-6) on the transcriptional profile of Pseudomonas aeruginosa.
- To identify the impact of these compounds on the expression of resistance-nodulation-division (RND) efflux pumps.
- To guide the rational design of future antivirulence therapies that circumvent resistance mechanisms.
Main Methods:
- Treatment of Pseudomonas aeruginosa strain PA14 with virulence inhibitors R-2 and R-6.
- Analysis of transcriptional profiles to assess gene expression changes.
- Comparative studies using wild-type and efflux pump-deficient strains.
- Evaluation of specific virulence factors such as swimming motility.
Main Results:
- R-2 and R-6 treatments induced differential expression of RND efflux pumps, specifically mexEF-oprN and mexAB-oprM, respectively.
- Certain chemical motifs in virulence inhibitors were found to increase RND efflux pump expression.
- In an efflux pump-deficient strain, R-2 and R-6 effectively inhibited virulence factors, including swimming motility.
- High efflux pump expression in wild-type strains suggests limited intracellular accumulation of the inhibitors.
Conclusions:
- The transcriptomic response to antivirulence inhibitors is complex and influenced by efflux pump activation.
- Identifying chemical features that trigger RND efflux pump expression is crucial for developing effective antivirulence drugs.
- Future drug design should focus on compounds that do not activate these resistance efflux pumps to maintain efficacy.
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