Longitudinal Analysis of the Fecal Microbiome and Resistome of Patients with Multidrug-Resistant Urinary Tract Infections and Predictors of Recurrence

PROJECT SUMMARY/ABSTRCTMultidrug-resistant organisms (MDRO) are major threats to human health, responsible for >2 million infectionsand 23,000 deaths per year in the US alone. Urinary tract infections (UTI) are the most common types ofinfections caused by MDROs. There are few options to prevent and treat MDRO UTIs, no interventions toreverse fecal MDRO colonization, and limited strategies to identify patients at risk for recurrence. This studywill address critical barriers to scientific progress in the fields of recurrent MDRO UTI and fecal MDROcolonization, and improve scientific knowledge by delineating the host microbial communities and MDRO traitsthat are associated with MDRO colonization and recurrent UTI.To advance my patient-oriented research career and pursue additional expertise in genomic research, I willconduct a prospective cohort trial of patients with MDRO UTIs and characterize their stool and urinespecimens utilizing microbiologic culture and genomic techniques. We will assess longitudinal changes in thefecal microbiome of patients with MDRO UTI utilizing metagenomic shotgun sequencing to identify microbialtaxa and functions associated with persistent MDRO colonization and recurrent UTI, and link this informationwith detailed clinical data. The proposals delineated here will advance the understanding of the microbialecology of the fecal microbiome and its role in MDRO infections, and will provide me the opportunity to gainknowledge and skills in study implementation, longitudinal data analysis, and genomic data analysis. I haveassembled a team of mentors and collaborators to guide my early research career and advise on theevaluation of existing stored specimens created through a pilot study, and ongoing recruitment of patients forthe prospective cohort trial. We will analyze the specimens to answer the following questions:1) What is the trajectory of the fecal microbiome and resistome in patients with MDRO UTIs after antimicrobialtreatment?2) Are there taxonomic and functional compositions of the fecal microbiome associated with MDRO colonization and recurrent infection?3) How does antimicrobial treatment impact the concentration of antibiotic resistance genes and bacterial virulence factors, and what is their relationship to recurrent MDRO UTI?Genomic approaches and classic microbiologic techniques will be used to assess the strain types, microbialtaxa, function, and antibiotic resistance genes found in the fecal microbiome of patients with MDRO UTIs. Theculmination of these studies will provide essential data to drive the rational design of methods to detect andprevent fecal MDRO colonization and MDRO UTIs. The findings in this study will be broadly applicable beyondUTIs, as we will determine the relationship between fecal MDRO colonization and recurrent infections.