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The analysis of the role of MexAB-OprM on quorum sensing homeostasis shows that the apparent redundancy of Pseudomonas aeruginosa multidrug efflux pumps allows keeping the robustness and the plasticity of this intercellular signaling network

Multidrug efflux pumps are key determinants for antibiotic resistance. Besides contributing to intrinsic resistance, their overexpression is frequently a cause of the increased resistance acquired during therapy. In addition to their role in resistance to antimicrobials, efflux pumps are ancient and conserved elements with relevant roles in different aspects of the bacterial physiology. It is then conceivable that their overexpression might cause a burden that will be translated into a fitness cost associated with the acquisition of resistance. In the case of Pseudomonas aeruginosa, it has been stated that overexpression of different efflux pumps is linked to the impairment of the quorum sensing (QS) response. Nevertheless, the causes of such impairment are different for each analyzed efflux pump. In this study, we performed an in-depth analysis of the QS-mediated response of a P. aeruginosa antibiotic resistant mutant that overexpresses MexAB-OprM. Although previous work claimed that this efflux pump extrudes the QS signal 3-oxo-C12-HSL, we show otherwise. Our results suggest that the observed attenuation in the QS response when overexpressing this pump is related to a reduced availability of intracellular octanoate, one of the precursors of the biosynthesis of alkyl quinolone QS signals. The overexpression of other P. aeruginosa efflux pumps has been shown to also cause a reduction in intracellular levels of QS signals or their precursors impacting on these signaling mechanisms. However, the molecules involved are distinct for each efflux pump, indicating that they can differentially contribute to the P. aeruginosa quorum sensing homeostasis. Importance The success of bacterial pathogens to cause disease relies on their virulence capabilities as well as in their resistance to antibiotic interventions. In the case of the important nosocomial pathogen Pseudomonas aeruginosa, multidrug efflux pumps participate in the resistance/virulence crosstalk since, besides contributing to antibiotic resistance, they can also modulate the quorum sensing (QS) response. We show that mutants overexpressing the MexAB-OprM efflux pump, present an impaired QS response due to the reduced availability of the QS signal precursor octanoate, not because they extrude, as previously stated, the QS signal 3-oxo-C12-HSL. Together with previous studies, this indicates that, although the consequences of overexpressing efflux pumps are similar (impaired QS response), the mechanisms are different. This ‘apparent redundancy’ of RND efflux systems can be understood as a P. aeruginosa strategy to keep the robustness of the QS regulatory network and modulate its output in response to different signals.