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Reducing Resistance: Determining Underlying Mechanisms Driving the Dissemination of Multidrug Resistant, Inca/c Plasmids

Lang, Kevin
University of Minnesota
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Multidrug resistance (MDR) in Gram-negative bacteria is becoming more prevelant among animal pathogens and bacteria associated with food-borne illness. Often times, the genetic determinants of MDR bacteria are carried on large, transferable pieces of DNA termed plasmids. Plasmids physically link genes that confer resistance to multiple classes of antibiotics and can transfer them in a single event. The A/C compatibility group (IncA/C) of plasmids has recently emerged and rapidly disseminated among enteric bacteria. Due to this rapid emergence, little is known about the basic biology of this plasmid type. The goal of this project is to better understand the biological relevance of regulatory networks encoded on large, MDR-encoding plasmids. Better understanding these mechanisms will aid in predicting and curtailing the emergence and dissemination of MDR bacteria.
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Multidrug resistance (MDR) is a global public health crisis. MDR bacterial infections are no longer only associated with hospital visits. The MDR-encoding plasmids belonging to the IncA/C incompatibility group have recently emerged among Escherichia coli and Salmonella enterica strains in the United States. These strains are increasingly observed in foodborne infections. IncA/C plasmids have been isolated from food animals, food products and animal infections. They pose a significant threat to public health due to their ability to confer resistance to many different antibiotics, including those used to treat serious infections. Despite the alarming speed at which they have spread and their association with pathogens, virtually no data exists pertaining to the basic biology on IncA/C plasmids. Nucleoid Associated Proteins (NAPs) are factors governing gene regulatory networks. Few studies have examined putative NAPs encoded on mobile genetic elements. IncA/C plasmids encode several putative NAPs. These proteins likely play critical roles in plasmid maintenance and spread. We propose to characterize these proteins in terms of their function and mechanism. The long term goal of this project is to better understand the biological relevance of NAP-associated regulatory networks encoded on IncA/C plasmids. Understanding novel factors involved in plasmid spread will aid efforts to curtail the spread of resistance determinants. Reducing exposure to MDR bacteria via the food supply will be a critical step for improved public health.

The long-term goal of this project is to better understand the biological relevance of gene regulatory networks carried on bacterial plasmids. To address this goal systematic deletions will be made to genes predicted to be involved with gene regulation on IncA/C plasmids. These mutations will be assessed on their impact to basic plasmid functionalities. Mutations which greatly impact the maintenance and plasmid transfer abilities will be further characterized. Targets identified in the first phase of the project will be examined in detail to define their mechanism of action. Most regulatory proteins act by binding DNA. ChIP-Seq will be used to map DNA binding sites specific to the target proteins. This is achieved by using deep sequencing technology to define the DNA that binds to specific proteins. Furthermore, transcriptional regulators often work in concert with each other. Therefore, using mass-spectrometry this project seeks to identify interactions between target proteins encoded on IncA/C plasmids.

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Nat'l. Inst. of Food and Agriculture
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Bacterial Pathogens