A biofilm is a community of microorganisms that can form on implanted medical devices leading to life threatening infections. Biofilms are also found within the lungs of patients with chronic pulmonary infections including patients with cystic fibrosis (CF) and are the major cause of morbidity and mortality in this patient population. The medical treatment of such infections is complicated by the fact that the constituent microorganisms of many biofilms display resistance to antimicrobial agents. Consequently, the persistence of microorganisms in biofilm growth mode, despite conventional antibiotic therapy, poses significant health threats to numerous patient populations. The basic goal of this proposal is to develop a safe and effective drug delivery system to kill bacteria growing in biofilms in the respiratory tract. The proposed delivery system is based upon nebulization, the process of aerosolizing therapeutic agents for delivery by inhalation to the respiratory tract. The treatment strategy is based upon silver-based antimicrobial compounds, in particular, silver carbene complexes (SCCs). Other potential therapeutic agents include silver-efflux inhibitors, anti-quorum sensing drugs, and enzymes that degrade the extracellular polymeric substances (EPS), or structural components of the biofilm. The proposed research will explore the efficacy of delivering these agents both in an aqueous solution, as well as in biodegradable polymer nanospheres. Agents delivered to the biofilm in soluble form enter the biofilm through its surface. The nanospheres, on the other hand, penetrate the biofilm through its cracks and pores, and then dissolve and slowly release the therapeutic agents over time. An interdisciplinary team of engineers, chemists, biologists, applied mathematicians, and a medical doctor will conduct the proposed research. Members of this team will synthesize novel silver carbene complexes as candidate antimicrobial agents, fabricate biodegradable polymeric nanospheres that contain silver-based complexes and other agents, perform in vitro and in vivo experiments to determine the efficacy of various compounds and delivery systems for treating biofilms of Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus (MRSA), and anthrax, and develop comprehensive mathematical models as a predictive tool for discovering effective treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086895-02
Application #
7674791
Study Section
Special Emphasis Panel (ZGM1-CBCB-5 (BM))
Program Officer
Okita, Richard T
Project Start
2008-08-15
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$327,920
Indirect Cost
Name
University of Akron
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
045207552
City
Akron
State
OH
Country
United States
Zip Code
44325
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Ditto, Andrew J; Shah, Kush N; Robishaw, Nikki K et al. (2012) The Interactions between L-tyrosine based nanoparticles decorated with folic acid and cervical cancer cells under physiological flow. Mol Pharm 9:3089-98
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Panzner, Matthew J; Bilinovich, Stephanie M; Youngs, Wiley J et al. (2011) Silver metallation of hen egg white lysozyme: X-ray crystal structure and NMR studies. Chem Commun (Camb) 47:12479-81

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