Abstract
Pseudomonas aeruginosa exhibits a broad spectrum of intrinsic antibiotic resistance because of the limited permeability of its outer membrane. Given this situation, molecules that could make Gram-negative bacteria more permeable and more susceptible to large-scaffold Gram-positive antibiotics may be advantageous. Herein, we evaluate the antimicrobial activity of a series of targeted poly(ethylene glycol)-desferrioxamine/gallium (PEG-DG) conjugates that can improve the sensitivity of P. aeruginosa to the glycopeptide vancomycin (VAN). We observed that single-ended mPEG-DG and double-ended PEG-DG(2) conjugates characterized by PEG MW ≥2000 synergistically enhanced the sensitivity of VAN against P. aeruginosa reference strains PAO1 and ATCC 27853 and three clinically isolated carbapenem-resistant strains, but not Escherichia coli strain ATCC 25922. Although the exact mechanism of this phenomenon is currently under investigation, PEG-DG conjugates enhanced nitrocefin (NCF), hexidium iodide (HI), and VAN permeability only when PEG and DG were directly conjugated. The two most important physicochemical factors contributing to the synergistic activity observed with VAN relate to (1) the final concentration of DG ligands conjugated to the polymer and (2) the polymer length, wherein MW ≥2000 yielded a similar fractional inhibitory concentration.