The bacteriophage-encoded regulator PemR attenuates Pseudomonas aeruginosa virulence by hijacking quorum sensing and metabolism

TL;DR

A phage-encoded protein called PemR reduces Pseudomonas aeruginosa virulence by disrupting quorum sensing and metabolism, offering a new anti-virulence strategy.

Contribution

PemR is the first reported phage-encoded transcriptional regulator that hijacks the mvfR regulon to attenuate bacterial virulence.

Findings

PemR represses the mvfR promoter, leading to reduced quorum sensing and virulence traits like pyocyanin and rhamnolipid production.

PemR redirects metabolism from PQS biosynthesis to catechol accumulation, causing global virulence attenuation.

PemR suppresses motility and modulates bacterial interactions in polymicrobial environments via upregulation of rsmA.

Abstract

The global challenge of multidrug-resistant Pseudomonas aeruginosa demands innovative anti-virulence approaches. We characterize PemR, a novel transcriptional regulator encoded by P. aeruginosa phage PAYQ66, which orchestrates multimodal virulence attenuation in P. aeruginosa. Biochemical analyses demonstrated that PemR directly binds to the mvfR promoter, resulting in significant repression of this key quorum-sensing regulator. This repression, in turn, induces profound metabolic reprogramming by redirecting metabolic flux away from PQS biosynthesis toward catechol accumulation. PemR globally attenuates virulence phenotypes, including pyocyanin production, rhamnolipid synthesis, motility, and biofilm formation. Transcriptomic profiling further reveals that PemR upregulates rsmA to suppress the type VI secretion system, thereby potentially modulating the host’s interaction with competing bacteria in polymicrobial environments. The motility analysis shows that PemR suppresses bacterial swimming, swarming, and twitching at gene expression levels. Overall, infection models demonstrate that PemR significantly inhibits bacterial virulence. As the first reported phage-encoded transcriptional hijacker of the mvfR regulon, PemR concurrently disrupts quorum sensing and bacterial pathogenicity, offering a strategic blueprint for novel anti-virulence therapeutics targeting multidrug-resistant pathogens.

This study identifies a novel bacteriophage-encoded regulator PemR that simultaneously disrupts multiple virulence pathways in the opportunistic pathogen P. aeruginosa. By hijacking a key bacterial quorum-sensing (QS) system and reprogramming host metabolism, PemR significantly reduces pathogenicity without killing the bacteria. This work reveals a sophisticated strategy phages use to manipulate their hosts and provides a promising blueprint for developing next-generation anti-virulence therapeutics. Such approaches aim to disarm dangerous bacteria rather than eliminate them, potentially slowing the emergence of antibiotic resistance and offering new strategies against multidrug-resistant infections.

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