Unlocking New Defenses: How Interrupting Bacterial Communication Could Combat Superbugs

Pseudomonas aeruginosa is a formidable adversary in the healthcare world, notorious for causing severe hospital-acquired infections, forming resilient biofilms, and demonstrating alarming resistance to many existing antibiotics. The CDC lists it as a serious threat, highlighting the urgent need for new treatment strategies.

            Instead of developing more antibiotics that directly kill bacteria and potentially accelerate resistance, scientists are exploring a novel approach: targeting bacterial communication: quorum sensing (QS). Quorum sensing allows bacteria to produce, release, and detect chemical signal molecules called autoinducers. As these autoinducers accumulate with increasing bacterial density, they trigger group-wide behaviors, including the production of toxins and the formation of biofilms—both crucial for P. aeruginosa pathogenicity. The idea is that "behavior modification" treatments, which prevent bacteria from acting as a group and causing disease without affecting their growth rate, may prevent or delay the evolution of resistance compared to traditional bactericidal treatments.

P. aeruginosa employs three main quorum-sensing systems, each involving an autoinducer : receptor pair: 3O-C12-HSL : LasR, C4-HSL : RhlR, and PQS : PqsR or HHQ : PqsR.  While LasR was initially a focus for inhibition, it often acquires inactivating mutations during chronic infections, allowing the Rhl system to maintain quorum sensing. This has shifted research efforts to target RhlR and PqsR for chronic P. aeruginosa infections.

            A key player in this intricate network is PqsR, which regulates the expression of the pqsE gene. Interestingly, the PqsE protein then interacts with RhlR, enhancing its activity and enabling it to activate a specific subset of virulence genes. This critical link makes PqsR an especially attractive target for small molecule inhibitors.

            The Bassler Lab at Princeton, in association with Duke University Medical Center, developed a specialized P. aeruginosa strain with a bioluminescent reporter system designed to detect inhibitors of PqsR and RhlR. Screening over 100,000 compounds, they identified 30 potent PqsR inhibitors. These compounds demonstrated high efficacy, with many showing activity in the nanomolar to low micromolar range and appear to function competitively by binding to the autoinducer site on PqsR. Importantly, these inhibitors effectively blocked PqsR activity without affecting bacterial growth, a crucial feature for anti-virulence therapeutics.

            The identified PqsR inhibitors work by suppressing the production of PqsE. This is significant because RhlR, another key quorum-sensing receptor, controls different sets of genes depending on whether it's bound to its own autoinducer, C4-HSL, or to PqsE. For instance, the production of pyocyanin, a toxic blue-green compound and a major P. aeruginosa virulence factor, is activated by PqsR:PQS. The research revealed that RhlR requires PqsE to activate the biosynthetic genes for pyocyanin (specifically phzS), while C4-HSL is dispensable for this particular pathway. By inhibiting PqsR, and consequently reducing PqsE, the newly discovered compounds specifically interfere with the PqsE-RhlR-controlled pathways, like pyocyanin production, but not the RhlR-C4-HSL-dependent ones.

           This work profoundly highlights the differential roles of PqsE and RhlI (which synthesizes C4-HSL) in controlling phenazine production. The findings underscore the immense promise of inhibiting PqsR as a potential therapeutic strategy to combat P. aeruginosa infections by suppressing virulence factors controlled by the RhlR-PqsE pathway. This strategy offers a hopeful path toward new anti-infectives that could overcome antibiotic resistance by disarming bacteria rather than simply attempting to kill them. Future research will focus on improving these PqsR inhibitors and further unraveling the complexities of differential phenazine regulation.

Valastyan JS, Shine EE, Mook RA, Bassler BL. Inhibitors of the PqsR Quorum-Sensing Receptor Reveal Differential Roles for PqsE and RhlI in Control of Phenazine Production. ACS Chem Biol. 2025 Jun 20;20(6):1273-1287. doi: 10.1021/acschembio.5c00114. Epub 2025 May 14. PMID: 40366200; PMCID: PMC12186256.

https://pubs.acs.org/doi/10.1021/acschembio.5c00114