Project Report

Bacteria and other microorganisms have evolved a number of strategies to overcome the defenses of the human immune system and successfully infect their host. In particular, Staphylococcus aureus is a common pathogen that, under specific circumstances, can lead to a number of conditions ranging from minor skin inflammation to infective endocarditis and death. In recent years, new strains of this pathogen have evolved that are resistant to traditional antibiotic medications. We have taken a novel approach to specifically target Staphylococcus aureus. Recent work has shown that the bacterium secretes a number of proteins, which contribute to its ability to infect its host. In particular, three structurally similar proteins interact with a protein of the complement immune system, which coordinates both innate and adaptive immune responses in order to recognize pathogens in the bloodstream. This complement protein, known as C3, is critical for activation of complement, and in turn, recognition and elimination of pathogens. Through interaction with C3, Staphylococcus aureus can prevent complement activation, and effectively disguise itself from the immune system. Most traditional antibiotics are nonspecific in nature, and target markers characteristic of all bacteria. We aim to develop a new antibiotic molecule specific for Staphylococcus aureus, based on knowledge of its immune evasion strategies. Based on the known structure of the protein interaction between C3 and secreted bacterial proteins, we have performed a virtual screen for small molecules that can disrupt these interactions. We have screened a public database of nearly 6 million drug-like molecules for binding to C3 using computational methods. Specifically, we first screened the database for molecules that have properties similar to the bacterial proteins that bind C3, followed by a more rigorous screen involving molecular docking simulations, which allowed each molecule to adopt a relaxed conformation in the interaction site on C3. Based on empirical force fields, the binding energy of each molecule was calculated, which served as an indicator of how strongly each molecule would bind C3. Our results yielded a number of molecules predicted to bind strongly to C3, which is promising for the discovery and development of a new specific therapeutic. The search for a new Staphylococcus aureus antibiotic via virtual screening remains widely unexplored. Our comprehensive integration of computational methods has led to the identification of predicted active molecules for treatment of bacterial infections. The molecules identified during this project are currently being evaluated experimentally, in order to determine whether they are capable of interacting with their intended target (C3) and disrupting its interaction with secreted bacterial proteins. This research provides a foundation for the development of a widely available and inexpensive treatment of infections caused by Staphylococcus aureus, which are responsible for widespread disease and mortality worldwide each year.

Agency
National Science Foundation (NSF)
Institute
Office of International and Integrative Activities (IIA)
Application #
1108556
Program Officer
Carter Kimsey
Project Start
Project End
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
Fiscal Year
2011
Total Cost
$5,700
Indirect Cost
Name
Gorham Ronald D
Department
Type
DUNS #
City
Riverside
State
CA
Country
United States
Zip Code
92507