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Molecular Mechanisms for Pathogen Emergence


The objective of this project is to understand the molecular genesis and emergence of antimicrobial resistance among bacterial pathogens. Research will focus on the role of mutators, specifically those deficient in methyl-directed mismatch repair, on establishing antimicrobial resistance by genetic change (mutation) and exchange (recombination).

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Recognizing that bacterial pathogen will continue to evolve, public health initiatives must include research to understand how these pathogens arise, propagate, and emerge. Bacteria have great ability to adapt rapidly and propagate to fill an existing niche. The role that antibiotics play in the emergence of antibiotic resistance bacteria has received ample attention, yet, the role of genetic diversity of a bacterial population or the effects of other selective pressures have on emergence of antibiotic resistance have not been adequately addressed. This project investigates the proposition that antibiotic resistant strains are emerging from specific "pools" that exist in bacterial populations at large. We have shown previously that high frequency (1-5%) of methyl-directed mismatch repair (MMR-) defective, pathogenic Escherichia coli and Salmonella enterica strains, exist and persist among natural populations. We will assess the role that MMR- mutators play in the emergence of antibiotic resistant strains by first determining the frequency of mutators among clinical and agricultural isolates of Salmonella. The nature of these mutator phenotype will be characterized and phylogenetic analyses will be done to assess whether clonal theory adequately addresses lineages observed among antibiotic resistant strains of Salmonella. Finally, we will explore if an MMR- phenotype can be enriched under experimental conditions using an in vivo murine infection model.

The impact of this project includes the development of rapid methods to detect and identify antibiotic resistance pathogens in our food supply and to aid in our understanding of how antimicrobial resistance emerges. Moreover, in order for intervention strategies to be effective, it is essential to understand the process of emergence to be able to predict if a certain pathogens will be in a unprocessed food and to explore processing parameters that will eliminate them. Finally, by identifying critical bacterial subpopulations (like the mutators) that are more apt to resist antibiotics and antimicrobials, appropriate containment procedures can be implemented before these strains are disseminated globally.

Cebula, Thomas
DHHS/FDA - Center for Food Safety & Applied Nutrition
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