Ligand lipophilicity-guided design of a Ga(III) complex with dual antiplanktonic and antibiofilm activity against Pseudomonas aeruginosa

The emergence of multidrug-resistant Pseudomonas aeruginosa (MDR) and its ability to form biofilms present major clinical challenges. Gallium (Ga³⁺), a redox-inactive iron mimic, disrupts bacterial iron metabolism and has shown promise as an antimicrobial agent. Here, we report the lipophilicity-guided design of Ga(phthiocolate)₃, a novel Ga(III) complex featuring a highly conjugated ligand scaffold that enhances membrane permeability. Ga(phthiocolate)₃ exhibits potent dual activity against both planktonic and biofilm-associated P. aeruginosa, including an MDR strain, with a minimum inhibitory concentration (MIC) of 5.0 μg/mL and a minimum biofilm eradication concentration (MBEC) of 20 μg/mL-only a fourfold increase over its MIC. The complex also synergistically potentiates meropenem (FIC index = 0.375), reducing its MIC eightfold. Mechanistic studies indicate that lipophilicity facilitates Ga³⁺ uptake and iron mimicry, leading to metabolic disruption and biofilm eradication. Ga(phthiocolate)₃ demonstrates low cytotoxicity and minimal hemolytic activity, supporting its potential as a next-generation antimicrobial agent for combating biofilm-associated infections and antibiotic resistance.