A Factor H-Fc Fusion Therapy for Methicillin-Resistant Staphylococcus aureus Infection
Abstract
Topic Area: Antibiotic Resistance Central Critical Problem: Staphylococcus aureus is a highly effective human pathogen that causes a wide range of infections that frequently result in significant morbidity and mortality and substantially contribute to healthcare costs. S. aureus is becoming increasingly resistant to antibiotics, which presents a major difficulty in treating S. aureus infections. For example, methicillin-resistant S. aureus (MRSA) is now found in more than 50% of S. aureus infections in healthcare settings and has emerged in the community with community-associated MRSA (CA-MRSA) infections reaching epidemic levels. As such, novel therapies for the treatment and prevention of S. aureus infection are in dire need. Overview of the Proposed Research Project: We propose to develop a new drug for MRSA, engineered from two human proteins, that will undermine the mechanism that S. aureus uses to evade detection and destruction by the human immune system. Complement is an important part of the human immune system that normally attaches to foreign organisms and marks them for destruction. S. aureus evades destruction by complement by binding a human complement regulator called Factor H (FH) to its surface. The binding of FH by S. aureus is advantageous to the bacterium as it inhibits the complement activity that would otherwise target the bacterium for destruction by a type of white blood cell called a polymorphonuclear cell. FH is comprised of 20 complement control protein modules (CCPs). CCPs 1-4 contain all of the complement inhibitory activity of FH, while CCPs 19-20 bind to the S. aureus surface. We have produced FH(18-20)/Fc, an engineered protein that combines the S. aureus-binding CCPs from FH with immunoglobulin Fc, an antibody fragment that activates complement on surfaces to which it is bound. In a preliminary experiment, we have shown that FH(18-20)/Fc binds to S. aureus. The purpose of this research project is to demonstrate the ability of FH/Fc to promote activation of complement on the surface of S. aureus, thereby leading to increased bacterial killing by polymorphonuclear cells. Using a plant expression system, we will produce FH(18-20)/Fc along with three control FH/Fc fusions: one with a mutation that eliminates Fc’s ability to activate complement and two more with modified Fcs designed to dramatically enhance complement-activating activity. We will first test how well FH(18-20)/Fc blocks binding of human FH to S. aureus. Next, we will measure how FH(18-20)/Fc bound to S. aureus affects complement activation. Finally, we will measure the efficacy of FH/Fc fusions in boosting killing of MRSA by human polymorphonuclear cells. Innovation: The innovation of our idea is turning a mechanism that S. aureus naturally uses to evade destruction by complement against itself. Because this approach undermines a mechanism crucial to MRSA’s survival in the human body, it may be difficult for the bacterium to evolve resistance to FH(18-20)/Fc. Ultimate Applicability and Impact: We expect that FH(18-20)/Fc can be developed into a novel treatment for MRSA infections. Future research projects will test using FH(18-20)/Fc to treat MRSA infections in animal models and later in human clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910119
Entities
People
- Keith Wycoff
Organizations
- Planet Biotechnology (United States)
- United States Army