Improved Biofilm Antimicrobial Activity of Polyethylene Glycol Conjugated Tobramycin Compared to Tobramycin inPseudomonas aeruginosaBiofilms

Abstract

The objective of this study was to develop a functionally enhanced antibiotic that would improve the therapeutic activity against bacterial biofilms. Tobramycin was chemically conjugated with polyethylene glycol (PEG) via site-specific conjugation to form PEGylated-tobramycin (Tob-PEG). The antibacterial efficacy of Tob-PEG, as compared to tobramycin, was assessed on the planktonic phase and biofilms phase of Pseudomonas aeruginosa. The minimum inhibitory concentration (MIC80) of Tob-PEG was higher (13.9 μmol/L) than that of tobramycin (1.4 μmol/L) in the planktonic phases. In contrast, the Tob-PEG was approximately 3.2-fold more effective in eliminating bacterial biofilms than tobramycin. Specifically, Tob-PEG had a MIC80 lower than those exhibited by tobramycin (27.8 μmol/L vs 89.8 μmol/L). Both confocal laser scanning microscopy and scanning electron microscopy further confirmed these data. Thus, modification of antimicrobials by PEGylation appears to be a promising approach for overcoming the bacterial resistance in the established biofilms of Pseudomonas aeruginosa.

Microcontainer Delivery of Antibiotic Improves Treatment of Pseudomonas aeruginosa Biofilms

“…reported a 3.2‐fold increase in elimination of an established P. aeruginosa biofilm when treated with PEG‐conjugated tobramycin compared to the effect of a solution of the antibiotic. [ 38 ] Moreover, Suk et al. showed that low MW PEG‐coated nanoparticles moved through undiluted cystic fibrosis sputum up to 90‐fold faster than uncoated particles, but the penetration of identically coated larger nanoparticles were strongly hindered.…”

The particle in the spider's web: transport through biological hydrogels

“…131 Furthermore, the relationship between charge-charge and hydrophobic interactions is not fully understood, and the chemical heterogeneity of biological gels lends the problem an additional layer of practical uncertainty. These difficulties notwithstanding, the cases of PEGylated tobramycin 132 and charge-reduced lysozyme 137–140 suggest that engineering drugs with hydrogel interactions in mind can improve efficacy. Engineering drug interactions with biological gels may also lead to new functional biocompatible hydrogels, sidestepping the need for complex synthetic formulations.…”

“…However, the improvement in activity of the PEGylated tobramycin against biofilms was modest, because the PEG chain compromised the biological activity of the molecule. 132 One possible strategy to avoid reduced activity is to make the PEGylation reversible via hydrolysis, a strategy that has been investigated for gentamicin (another aminoglycoside) due to the potentially improved pharmacokinetic properties offered by PEGylation, but not studied in a biofilm context. 133 Reversible PEGylation may allow for gel penetration, as well as full activity of the hydrolyzed form.…”

A combinatorial biomolecular strategy to identify peptides for improved transport across the sputum of cystic fibrosis patients and the underlying epithelia

“…To query the transport of the identified peptides in the CF sputum microenvironment, we conjugated synthetic peptides to carboxyl-modified polystyrene nanoparticles of 100 nm diameter and compared their mean squared displacement (MSD) in patient sputum with nanoparticles conjugated to mPEG 1 kDa. Recent studies have shown hydrophilic, net-neutral charge PEG polymer and polymer conjugates can improve transport of particles in CF sputum up to 90-fold compared to uncoated particles and improve therapeutic activity of antibiotics such as tobramycin against bacterial biofilms commonly associated with CF infections [17,[81][82][83].…”