We are pleased to announce that Minh-Hong Nguyen, MD, has been awarded funding in the amount of $440,431 for a two-year grant by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) entitled, “Within-host diversity of Gram negative bacteria from bloodstream infections.” This proposal was submitted in response to the competitive funding opportunity entitled, “NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trials Not Allowed)” under funding opportunity number PA-20-195. 

Gram negative bacilli (GNB) are major human pathogens, which have a propensity to develop antimicrobial resistance (AMR). Bloodstream (BSIs) and other serious GNB infections are usually caused by strains that colonize the gastrointestinal (GI) or respiratory tract. Emerging whole genome sequence (WGS) data show that the GI/respiratory tract is colonized by clonal bacterial populations, in which genetic diversity develops. It is unknown how often BSIs are caused by clonal but genetically diverse strains of a given bacterium, since clinical labs generally characterize a single colony from positive cultures. In preliminary studies, Drs. Nguyen/Clancy and their team performed WGSing on strains isolated from 10 independent colonies from carbapenem-resistant KP (CRKP)-positive blood cultures of 6 patients. In all patients, blood cultures contained genetically distinct sequence type-258 CRKP strains, as evident by core genome single nucleotide polymorphisms, gene deletions and other mutations, and plasmid or plasmid-borne gene loss. Genetically distinct CRKP strains exhibited significant differences in antibiotic tolerance and AMR, capsular polysaccharide content, and other virulence-associated phenotypes. It is unclear whether the findings were unique to CRKP BSIs, which typically occur in patients who face significant selection pressures from long-term antibiotic use and other stressors, or if the findings carry clinical significance. In this project, the team will determine genetic and phenotypic diversity among strains from BCs of patients diagnosed with antibiotic susceptible (S)-GNB BSIs, and investigate whether such diversity has clinical relevance. 

This project is conceptually innovative in challenging the long-accepted “single-organism” paradigm of bacterial BSIs. Medical and clinical microbiology lab practices have been built largely upon identifying a putative causative bacterium, against which specific antimicrobials can be administered and pathogenic mechanisms can be investigated. Anticipated findings of within-host genotypic and phenotypic microbial diversity during S-GNB BSIs would indicate that these phenomena are not limited to the most highly resistant infections. The project will serve as a model for studies of microbial diversity during other types of infection, and during BSIs due to diverse pathogens.

Congratulations, Hong!