The World Health Organization and U.S. Centers for Disease Control and Prevention have designated antimicrobial resistance a major threat to Global Health with over 23,000 annual deaths related to antimicrobial resistant infections in the U.S. alone. However, the drug pipeline to develop new antibiotics is dry. Small studies support the safety and efficacy of fecal microbiota transplantation (FMT) to eliminate intestinal colonization with antibacterial resistant organisms but its mechanisms are not well understood. We will leverage patient-linked samples from a clinical trial PREMIX (NCT02922816) to test our overarching hypothesis that anaerobic bacteria, viruses, and their gene-predicted functions are causally associated with decreased MDRO colonization after FMT.
The Specific Aims of this proposal include:
Aim 1 : Use the clinical gold standard of bacterial culture to estimate efficacy of FMT in MDRO eradication.
Aim 2 A: Establish a novel metagenomic analytic pipeline (MAP) to quantify abundance of bacterial and viral taxa, AR, virulence, and colonization resistance genes.
Aim 2 B: Use 16S rRNA sequencing to estimate temporal dynamics of difficult to culture bacterial taxa in FMT vs controls.
Aim 2 C: Use metagenomic whole-genome sequencing and the MAP to estimate temporal dynamics of AR, virulence, and colonization resistance genes in FMT vs controls.
Aim 3 : Use environmental virome NGS techniques to test the association of viral (including bacteriophage) taxa with abundance of MDRO after FMT. We expect that completion of these aims and related training will lead to clinically applicable preliminary data and next steps in translational microbial therapeutic development for MDRO colonization. My long-term career goal is to become a collaborative leader in ID microbiome data science focusing on: 1) mechanisms of microbial therapeutics such as FMT in reducing colonization with multi- drug resistant organisms (MDRO), and 2) translating these findings into clinical and public health interventions to reduce MDRO colonization and infection. Emory and Georgia Tech are ideal and highly-collaborative research environments, which are both national leaders in biomedical research. Both institutions provide rich resources to complete the described aims and progress in career development to become an independent translational ID microbiome data scientist. In addition, Emory is an active site of microbial therapeutic investigation with 7 clinical trials of microbial therapeutics and a clinical FMT program that has completed over 300 treatments for refractory Clostridioides difficile.

Public Health Relevance

Antimicrobial resistance has been declared a major threat to global health by the World Health Organization and over 23,000 people die from antibacterial-resistant infections each year in the United States. This career development award proposal leverages patient-linked samples from an ongoing clinical trial (NCT02922816) to begin to identify causal mechanisms of the established efficacy of fecal microbiota transplantation in treatment of intestinal antimicrobial resistant organism colonization. Findings from the described aims could inform next steps in development of targeted microbial therapeutics to directly address the mounting threats of antimicrobial resistance.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Mentored Patient-Oriented Research Career Development Award (K23)
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Microbiology and Infectious Diseases B Subcommittee (MID)
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Ranallo, Ryan
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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