Genomic Analysis of Multidrug Resistance in Esbl-Positive and Carbapenem-Resistant Bacterial Pathogens

The long-term goals of this work are to improve our understanding of the changing nature of antibiotic resistance and to support development of molecular assays to improve diagnosis and treatment selection for infections. This will be pursued in two ways.

First, we will assess genetic mechanisms involved in emergence of antibiotic resistance in nosocomial pathogens. Genome sequencing will be performed on carefully selected collections of historical and current isolates from geographically diverse regions. Isolates will have adequate metadata on resistance phenotype and clinical characteristics to enable genotype-phenotype associations. The project is designed to address the following driving questions: 1) How many infections result from patient-to-patient transmission vs from a diverse pool of commensal or environmental strains? 2) Does resistance emerge on certain strain backgrounds? 3) How much of resistance is explained by acquired mutations?

Second, we will explore variation in DNA methylation patterns and the role of DNA modification in modulating of bacterial gene expression. Analysis of DNA base modifications is an area of rapid technical advancement. Base modifications are highly variable across species and associated with numerous biological processes including replication and transcriptional regulation. We will explore the scope of DNA base modifications with an emphasis on candidate DNA methyltransferases encoded on mobile elements and on the effect of antibiotic exposure on modification and gene expression.

Supplemental Projects

• Diarrheal pathogens - metagenomic epidemiology of antibiotic resistance in infectious diarrhea
• Streptococcus pneumonia - supporting respiratory microbiome analysis in a H3Africa study (U01 AI110466, Mark Nicol/ Heather Zar)
• Non-tuberculosis Mycobacteria - sequence and analysis of Non-Tuberculous Mycobacteria (NTM) strains
• Sequencing of new strain collections to understand clinical outcomes of CR-Klebsiella pneumoniae infections throughout the USA
• Bioinformatics tool development as relates to AMR
• Targeting horizontal gene transfer events of mobile elements (ME) associated with AMR genes
• Sequencing and pan-genomics of global strain collections to understand the mechanism(s) of transmission and spread of carbapenem resistant Enterobacteriaceae

Funding