Modifying Heterocycles to Treat Gram + and Gram - Bacteria
Abstract
The rise of infections caused by bacteria resistant to traditional antibiotics is a real cause of concern to mankind. Bacterial infections caused by toxic pathogens can have devastating effects including limb amputations and death. Bacteria are mainly divided into two types: gram positive and gram negative. The latter possess two membranes that have the ability of preventing the passage of antibiotics, thus limiting their action. Our goal is to prepare new antibiotics based on natural products known as phenazines. We seek to create new broad-spectrum antibacterial drugs to address the following topic area “Development of novel and/or innovative interventions, diagnostics, and treatment for multidrug-resistant pathogens.” Phenazines have been known for many years as small molecules that are able to kill bacteria. However, they have not successfully hit the market because of some limitations including lack of specificity (they can be toxic to cells in the body) and poor water solubility. We propose to modify these phenazine molecules with simple structures such as amines (many of them naturally found in the body) and with peptides made of natural amino acids. Scientists have recently shown that adding these groups can increase the potency of antibacterial entities. Also, because all of these molecules interact with water, our expectation is that these changes will increase the aqueous solubility of the molecules. We will use simple medicinal chemistry to prepare the compounds and then evaluate their ability to kill dangerous bacteria. Next, we will study the toxicity of the molecules against various human cells to ensure that the compounds will not be toxic to humans. Finally, we will use two simple infection models, based in worms, that replicate some of the features found in human infections to study the efficiency of the new compounds. If this project is a success, we will have a new set of potent drugs that are able to treat dangerous bacterial infections. Given the cost and consequences derived from bacterial infections, a new antibiotic that kills as many pathogens as possible at low doses can have a lasting impact in society.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810113
Entities
People
- Martin Conda-Sheridan
Organizations
- United States Army
- University of Nebraska Medical Center