Developing Novel Tools for Detecting Antibiotic-Resistant Pathogens and Dissecting Evolution of Antibiotic Resistance
Abstract
Our proposal focuses on the Topic Area of “Antimicrobial Resistance,” and the ultimate goal of this research proposal is to develop technologies for rapid detection of antibiotic-resistant bacteria and to better understand the evolutionary dynamics of antibiotic resistance. Antibiotics have revolutionized clinical medicine and saved countless lives. For instance, cancer and bone marrow transplants patients who used to frequently die from bacterial and fungal infections (as a consequence of chemotherapy that suppresses their immune system) have been protected through the use of prolonged antibiotic therapy. This, however, is a double-edged sword as we now witness the increasing number of antibiotic-resistant bacteria infecting patients. Evolution of antibiotic resistance is a complex problem that is exacerbated by inflated use of antibiotics in agriculture and medicine, lack of information and resources, increased human mobility across the worlds, and reducing number of novel antimicrobial compounds in the past decade. Developing novel antibiotics has been a practical solution for combating antibiotic resistance in the past. However, the solution to this problem goes beyond the search for new antimicrobials: every antibiotic compound, regardless of its mechanism of action, is prone to fail due to emerging resistance, especially if not used carefully. Therefore, there is a desperate need for new strategies that will effectively use existing or future antibiotics, taking the evolution of antibiotic resistance into account from the start. These strategies should offer the ability to increase the clinical efficacy of antimicrobials and a way to minimize the rate at which resistance evolves. Rapid detection and characterization of disease-causing bacteria and a better understanding of how antibiotics lead to resistance will be critical in finding such strategies. We propose an innovative project that aims to develop novel tools for rapid detection and identifying of disease causing bacteria and for better understanding of evolution of antibiotic resistance. These tools will help us prescribe which specific antibiotics or antibiotic combinations can minimize the likelihood of antibiotic resistance evolution, while still providing maximum protection for patients. For this goal, we will use the RUSD (Rapid UltraSensitive Detector) and killostat platforms. To explore these questions, we have developed the following three specific aims. First, we will develop a label-free and low-cost fiber-based instrument that we call the RUSD. The small size and the light weight of RUSD will make it field-deployable and allow health workers to rapidly identify bacteria in body fluids and drinking water. RUSD will not be only used for bacterial detection but will also be used for rapid characterization of bacteria isolated from patients. Second, we will develop an experimental platform that we call the “killostat” that can recapitulate evolution of antibiotic resistance in pathogenic bacteria. The killostat will be a powerful system that provides an “in vitro lens” for observing the evolution of resistance, and lets us create a connection between evolutionary insights and the clinical setting. Third, by using the killostat, we will elucidate the mechanisms by which specific antibiotics or antibiotic combinations can minimize the likelihood of antibiotic resistance evolution in Staphylococcus aureus, an important pathogen that is responsible for thousands of deaths worldwide, while still providing maximum protection for the host. The short-term impact of this proposal is that it will lead to development of novel tools that can detect antibiotic-resistant bacteria and recapitulate evolution of resistance. The long-term impact is that the knowledge gained from this project may allow us to weather bacterial infections with minimal damage, that is, to treat patients with specific antibiotic regimens that maximally protect the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810127
Entities
People
- Erdal Toprak
Organizations
- United States Army
- University of Texas Southwestern Medical Center