The incidence of antibiotic resistant infections is rapidly increasing. This trend, coupled with the fact that only two new classes of antibiotics have been introduced in the last two decades and many pharmaceutical companies have discontinued their antibiotic research efforts, have led to a situation in which many bacterial infections are extremely difficult/impossible to treat. To combat these multi-drug resistant pathogens, we have posited that conjugating resistance-compromised drugs to the surface of gold nanoparticles will deliver active antibiotic conjugates that overcome typical antibiotic resistance mechanisms. To validate this hypothesis, we will design doxycycline-conjugated gold nanoparticles that maintain their ability to bind 30S RNA but do not activate tetracycline resistance. We will also demonstrate that these particles potently inhibit growth of tetracycline resistant bacteria. To achieve this goal, the two specific aims of this proposal are: 1) To design and synthesize a thiolated tetracycline derivative for conjugation to a gold nanoparticle and 2) Evaluation of antibacterial properties and TetR binding discrimination.

Public Health Relevance

The Center for Disease Control has indicated that virtually all significant bacterial species in the world are becoming resistant to antibiotic treatment regimens, and estimates that each year 2 million people in the US will acquire an infection while in a hospital (HAI), resulting in 100,000 deaths. These HAIs are estimated to result in $30 billion of direct costs annually.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI096015-02
Application #
8263747
Study Section
Special Emphasis Panel (ZRG1-BST-K (02))
Program Officer
Korpela, Jukka K
Project Start
2011-05-15
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$178,713
Indirect Cost
$25,968
Name
North Carolina State University Raleigh
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Worthington, Roberta J; Melander, Christian (2013) Combination approaches to combat multidrug-resistant bacteria. Trends Biotechnol 31:177-84
Worthington, Roberta J; Melander, Christian (2013) Overcoming resistance to *-lactam antibiotics. J Org Chem 78:4207-13