Online

Hinkel, Lauren Alexandra

Cellular, Molecular, and Biomedical Sciences Graduate Program

2020

Ph. D.

The increase in multidrug resistance (MDR) among bacterial pathogens is an ongoing threat to public health, with the CDC estimating more than 2.8 million MDR infections in the United States each year, and greater than 35,000 deaths annually. Gram-negative bacteria possess intrinsic mechanisms to resist available therapeutics and are frequently responsible for difficult-to-treat nosocomial, blood stream, and soft tissue infections. In addition to biophysical and genetic MDR mechanisms, Gram negatives are metabolically versatile, enabling them to utilize host-derived nutrients to promote proliferation and colonization within the host. The metabolic versatility of Gram-negative bacteria is due, in part, to the transcription of a diverse array of compound-specific transcriptional regulators, which facilitate the integration of extracellular signals into transcriptional changes. This ability to adjust to a changing extracellular environment contributes to the success of a bacterium as an opportunistic pathogen. Many opportunistic pathogens are found in environmental reservoirs and evolve or acquire mechanisms within these competitive niches that are also effective during host-infection. Some of these multipurpose systems pertain to the utilization of host-derived compounds. While the title 'host-derived' suggests that these compounds are exclusively encountered as integral parts of the host, bacteria also encounter host-derived compounds in other contexts, such as within soils or aquatic ecosystems. The compounds focused on in this dissertation can be derived from within the host, but are also found within environmental niches. Here we investigate, through genetic, transcriptomic, and biochemical approaches, how three Gram-negative bacteria of varying degrees of virulence, Pseudomonas putida, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, interact with several host-derived compounds, including creatine, sphingosine, and mucin. It is important to gain a deeper understanding of how bacteria utilize these host-derived compounds, and how this utilization effects the transition to and exploitation of the host during infection, with the ultimate goal of identifying new avenues for therapeutic intervention.