Permeabilize, but Choose Wisely: Selective Antibiotic Potentiation Through Outer Membrane Disruption in Pseudomonas aeruginosa

Most clinically used antibiotics exert their effects by targeting essential intracellular components of bacterial cells. Therefore, enhancing their ability to traverse the bacterial envelope is crucial for restoring or improving therapeutic efficacy. We investigated the potential of outer membrane (OM)-disrupting agents-EDTA, NV716, colistin, and squalamine-to potentiate antibiotic activity against the multi-drug-resistant pathogen <i>Pseudomonas aeruginosa</i>. Our objective was to assess the therapeutic value of this strategy while also delineating its limitations by comparing responses across antibiotic classes with diverse chemical structures and pharmacological profiles. Beyond lipophilicity, we analyzed three additional physicochemical descriptors likely to influence OM permeability: molecular surface area, polarizability, and polar surface area. Our findings offer practical insights for the rational design of antibiotic-adjuvant combinations. While each descriptor provides valuable interpretive information, none alone reliably predicts OM-mediated potentiation. Instead, these factors should be viewed collectively within a multidimensional physicochemical profile, where optimal ranges of size, polarity, and lipophilicity act synergistically to enhance antibiotic uptake. By defining a shared multidimensional "responsive zone," we propose a framework to guide the selection or design of antibiotics compatible with OM-disrupting strategies, potentially enabling the repurposing of antibiotics limited by poor OM permeability.