Predicting Antibiotic Resistance: Moving from Reaction to Preemption of Emerging Pathogen Threats
Abstract
The rise of multi-drug resistant pathogens and their development for use in bioterrorism is a continuing and ever-present threat that requires innovative approaches to generate new counter-measures to Weapons of Mass Destruction (WMD), improve patient outcomes, and provide the basis for warfighter protection. With previous DTRA support, we developed a high-throughput pipeline approach to understand how pathogens adapt to current antibiotic countermeasures. Using this methodological pipeline, we are identifying and ranking the importance of specific genetic changes associated with the development of antibiotic resistance in pathogens, such as Francisella tularensis and Pseudomonas aeruginosa, that are of high relevance as WMDs or that may be present in the hostile environments experienced by warfighters in future operations. Compounding the danger of biological WMDs is the reality that warfighters are exposed to a wider range of naturally occurring and manmade pathogens than the civilian population. We have developed a rapid and scalable approach to identify and predict emergent antibiotic resistance that can be used to anticipate the need for new antibiotics, develop appropriate clinical drug regimens, and provide the biochemical targets for their development. As our approach identifies the majority of the potential evolutionary trajectories to resistance, we are able to reconstruct both common and less frequent genetic networks of adaptation and identify specific high-value nodes (genes that are common links to many pathways to resistance) as specific candidates for comprehensive characterization by biophysical and biochemical approaches. We are studying the following WMD-relevant pathogens and antibiotics: Pseudomonas aeruginosa with colistin, Nocardia nova with trimethoprim-sulfamethoxazole, and Francisella novicida with ciprofloxacin and doxycycline. From these studies we, and others in the community, can develop specific assays for the creation of new antibiotics or evaluate the efficacy of new drug combinations. The techniques we use for these pathogens can be extended to any culturable organism and can be broadly applied to other Department of Defense activities to combat WMDs and limit the spread of multi-drug resistant pathogens.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- May 26, 2016
- Source ID
- HDTRA11510069
Entities
People
- Yousif Shamoo
Organizations
- Defense Threat Reduction Agency
- Rice University