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PEGylation of tobramycin improves mucus penetration and antimicrobial activity against Pseudomonas aeruginosa biofilms in vitro Tania F. Bahamondez-Canas, Hairui Zhang, Frederic Tewes, Jasmim Leal, and Hugh D. C. Smyth Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00011 • Publication Date (Web): 07 Mar 2018 Downloaded from http://pubs.acs.org on March 8, 2018
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Molecular Pharmaceutics
PEGylation of tobramycin improves mucus penetration and antimicrobial activity against Pseudomonas aeruginosa biofilms in vitro
Tania F. Bahamondez-Canasa, Hairui Zhanga, Frederic Tewesb, Jasmim Leala, Hugh D.C. Smytha,c,*
*
Corresponding author: Address : 2409 University Ave, A1920 Austin, Texas 78712, United States Phone : +1 (512) 471 3383 Fax : +1 (512) 471 7474 E-mail :
[email protected].
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a
Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University
of Texas at Austin, Austin, Texas 78712, United States b
INSERM, U1070, UFR de Médecine Pharmacie, Université de Poitiers, 86073 Poitiers Cedex
9, France c
Center for Infectious Disease, The University of Texas at Austin, Austin, Texas 78712, United
States
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Molecular Pharmaceutics
ABSTRACT GRAPHIC
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ABSTRACT Pseudomonas aeruginosa is the predominant pathogen in the persistent lung infections of cystic fibrosis (CF) patients among other diseases. One of the mechanisms of resistance of P. aeruginosa infections is the formation and presence of biofilms. Previously, we demonstrated that PEGylated-tobramycin (Tob-PEG) had superior antimicrobial activity against P. aeruginosa biofilms compared to tobramycin (Tob). The goal of this study was to optimize the method of PEGylation of Tob and assess its activity in an in vitro CF-like mucus barrier biofilm model. Tob was PEGylated using three separate chemical conjugation methods and analyzed by 1H NMR. A comparison of the Tob-PEG products from the different conjugation methods showed significant differences in reduction of biofilm proliferation after 24h of treatment. In the CF-like mucus barrier model, Tob-PEG was significantly better than Tob in reducing P. aeruginosa proliferation after only 5 h of treatment (p
