Reengineering of Antibiotics Informed by Antimicrobial Resistance Mechanisms
Abstract
Topic Area: Antimicrobial Resistance A major cause of hospital-acquired bacterial infection is the “superbugs” MRSA (or methicillin-resistant Staphylococcus aureus) and VRE (vancomycin-resistant Enterococcus). Although MRSA infections were once readily treatable, MRSA and VRE are acquiring resistance to all antibiotics. The US Centers for Disease Control and Prevention estimates over 80,000 cases per year, with 13% chance of mortality. Globally, the World Health Organization warns that patients who contract antibiotic-resistant forms of this bacterium are 64% less likely to survive the infection. Perhaps most concerning is the fact that since 2001 there have been increasing cases of these superbugs that have evolved resistance to the last-resort antibiotic, linezolid. With respect to military relevance, Service members are more at risk of injury than the general population, placing a huge burden on the military hospital system. Therefore, there is an urgent need to develop a new generation of antibiotics effective against these infections, not just for hospital patients and wounded Service members, but for the community at large. A major barrier to overcoming antimicrobial resistance is the fact that we have a poor understanding of how these bacteria become resistant. A major target of antibiotics is the ribosome, the “cellular machine” that controls protein synthesis. In this project, we address this issue by applying cutting-edge imaging technology to link changes in the bacteria’s DNA to the changes in the molecular structure its ribosome that allow it to overcome antibiotic treatment. We will achieve this by imaging the ribosomes from clinical bacterial isolates, which have become resistant to the most modern antibiotics. Studying the architecture changes to this molecular machine that prevent antibiotics will provide the amazing insight into how bacteria become resistant. We will study a range of clinical isolates to be able to uncover some of the major escape routes that bacteria use on the road to becoming a superbug. This is an innovative approach to the study of antimicrobial resistance as we will be delving into the deep molecular principles as to how these superbugs evolve their resistance. The innovation also lies in how this molecular structure-based survey will generate unprecedented understanding of how we could design the next generation of antibiotics to maintain activity in the face of antibiotic resistance. We will test these ideas by chemically making new antibiotics that we predict will bind and block the function of the resistant bacteria. This study will represent the first of its kind where we take feedback from how bacteria escape antibiotic treatment and feed it straight back into the chemical design of more effective antibiotics. We will use this knowledge about how bacteria develop resistance to antibiotics to enable us to engineer new forms of antibiotics that will mitigate this resistance. This project is of significance as a guiding light in the development of the next generation of broad-spectrum antibiotics that remain effective against superbugs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910126
Entities
People
- Matthew Belousoff
Organizations
- Monash University
- United States Army