Enhancing outer membrane permeability of tetracycline antibiotics in using TOB-CIP conjugates.

is an opportunistic critical 'priority 1' Gram-negative bacterium that poses a severe threat to public healthcare due to rising antibiotic resistance. Particularly, low membrane permeability and overexpression of efflux pumps in lead to intrinsic resistance that compromises the antibacterial activity of antibiotics. The broad-spectrum antibiotics class, tetracyclines, are rarely used to treat 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 isolates. The structure-activity relationship investigation indicates that the flexible hydrophobic C carbon-chain linker in TOB-CIP conjugate 1a is an optimal potentiator of tetracyclines against tetracycline-resistant and -susceptible strains of Furthermore, conjugate 1a consistently synergized with the 3rd generation tetracycline, eravacycline, in PAO1 in the presence of up to 25% fetal bovine serum (FBS).