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The study focuses on enhancing the outer membrane permeability of tetracycline antibiotics in Pseudomonas aeruginosa using TOB-CIP conjugates. P. aeruginosa's low membrane permeability and efflux pump overexpression contribute to antibiotic resistance. The conjugates, particularly TOB-CIP conjugate 1a, effectively potentiate tetracycline antibiotics against multidrug-resistant P. aeruginosa isolates. The research highlights the importance of the C12 carbon-chain linker in the conjugate's structure-activity relationship and its synergistic effects on eravacycline, a 3rd generation tetracycline, even in the presence of fetal bovine serum.
Pseudomonas aeruginosa is an opportunistic critical ‘priority 1’ Gram-negative bacteria that poses a severe threat to public healthcare due to rising antibiotic resistance. Particularly, low membrane permeability and overexpression of efflux pumps in P. aeruginosa lead to intrinsic resistance that compromise the antibacterial activity of antibiotics. The broad-spectrum antibiotics class, tetracyclines, are rarely used to treat P. aeruginosa infections. In the present study, we describe a series of tobramycin-ciprofloxacin (TOB-CIP) conjugates in which the carboxylic acid of ciprofloxacin is linked to the aminoglycoside tobramycin using various tethers thereby generating a cationic amphiphile. The emerging amphiphilic conjugates potentiate tetracycline antibiotics including minocycline, doxycycline, tigecycline, and eravacycline against multidrug-resistant P. aeruginosa isolates. The structure-activity relationship investigation indicate that the flexible hydrophobic C12 carbon-chain linker in TOB-CIP conjugate 1a is an optimal potentiator of tetracyclines against tetracycline-resistant and -susceptible strains of P. aeruginosa. Furthermore, conjugate 1a consistently synergized the 3rd generation tetracycline, eravacycline, in P. aeruginosa PAO1 in the presence of up to 25% fetal bovine serum (FBS).
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