Gene Duplication and Amplification in the Evolution of Antimicrobial Resistance: Clinical Significance and Diagnostic Potential
Abstract
Antimicrobial resistance is a recognized and growing public health threat, with the potential to be exploited as an agent of bioterrorism. Antimicrobial resistance of clinically relevant microbial pathogens threatens to undermine many medical advances of the past century, including cancer therapy, organ transplantation, and even routine surgery. Understanding the biological mechanisms that mediate the development of resistance is crucial for the development of novel diagnostics to identify and treat these resistant pathogens. Gene duplication and amplification (GDA) is one mechanism implicated in the development of antimicrobial resistance. In this program, we are determining the clinical relevance of GDA in the development of antimicrobial resistance, and further, developing diagnostic techniques for the early identification of these resistant pathogens. We are working to identify signatures of GDA in clinical bacterial pathogens, both experimentally and through computational meta-analysis. In parallel, we are generating engineered bacterial strains to facilitate in vitro follow-up studies. Further, we are characterizing the biological mechanism by which GDA mediates antimicrobial resistance, through simultaneous analysis of gene dosage, and in vitro and in vivo experimental evolution. Additionally, we plan to exploit these previous analyses to identify novel biomarkers of GDA-mediated resistance in bacterial populations, to serve as diagnostic tools for resistant infections. Together, this will lead to improved diagnostics for the detection of nascent antimicrobial resistant infections.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 26, 2016
- Source ID
- HDTRA11510051
Entities
People
- James J. Collins
Organizations
- Defense Threat Reduction Agency
- Harvard University