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.
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.
|Worthington, Roberta J; Melander, Christian (2013) Overcoming resistance to ?-lactam antibiotics. J Org Chem 78:4207-13|
|Worthington, Roberta J; Melander, Christian (2013) Combination approaches to combat multidrug-resistant bacteria. Trends Biotechnol 31:177-84|