Broadly Defined Antibiotic Adjuvants for Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a widely distributed opportunistic pathogen with multiple drug resistance, making it particularly challenging to treat in lower respiratory tract infections. Its resistance mechanisms are complex, including low outer-membrane permeability, efflux pump overexpression, biofilm formation, and quorum sensing (QS) activation. Antibiotic adjuvants, as a strategy to enhance antibiotic efficacy and rapidly mitigate antibiotic resistance, have garnered significant attention. However, the traditional definition of antibiotic adjuvants typically refers to compounds like tazobactam, which lack inherent antibacterial activity but enhance the effects of antibiotics. This narrow definition emphasizes specific strategies to overcome P. aeruginosa resistance while excluding many promising approaches that enhance antibiotic activity through specific or nonspecific mechanisms. In this review, antibiotic adjuvants are defined as compounds coadministered or covalently linked with antibiotics to enhance the activity of the antibiotics. This review summarizes progress in research on "broadly defined antibiotic adjuvants" targeting P. aeruginosa and focuses on the following strategies: (1) enhancing outer-membrane permeability to facilitate antibiotic entry into the bacterial cell; (2) efflux pump inhibitors (EPIs) to inhibit the bacterial efflux of antibiotics from the periplasm; (3) the "Trojan Horse" strategy, utilizing siderophores or their analogs to deliver antibiotics into bacteria; (4) quorum sensing inhibitors (QSIs), which weaken P. aeruginosa pathogenicity and resistance by blocking QS signaling pathways; and (5) activation of persister cells to enhance the bactericidal effects of antibiotics on persister cells in biofilm, facilitating the elimination of P. aeruginosa in chronic infections. These strategies provide a theoretical foundation for developing novel antibiotic adjuvants, which may contribute to addressing the challenge of P. aeruginosa resistance and improving clinical treatment outcomes.