Graduate Thesis Or Dissertation

 

Exploiting Innate Immunity and Anti-infectives to Treat Intracellular Pathogens Public Deposited

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https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/qj72p853z
Abstract
  • Bacterial pathogens are increasingly resistant to our antimicrobial arsenal. Gram-negative bacteria are particularly problematic because of their robust cell envelope that excludes many antimicrobial agents. Moreover, intracellular Gram-negative pathogens take advantage of a niche within mammalian cells where they are shielded from the host’s adaptive immunity and the action of many antibiotics. Without antibiotic intervention, infected people can become lifelong bacterial reservoirs and can cause outbreaks. Thus, Gram-negative intracellular pathogens are a public health concern.

    Work here focuses on the Gram-negative intracellular pathogen, Salmonella Typhimurium that, within cells from the monocyte lineage, resides in a vesicle known as the Salmonella Containing Vacuole (SCV). During infection, the SCV fuses with the host phagolysosome, and S. Typhimurium are bombarded with a variety of insults including pH < 5.0 and antimicrobial peptides that disrupt the robust cell envelope. S. Typhimurium is normally capable of overcoming these insults to continue its infection.

    I have discovered different molecular mechanisms by which two novel compounds, JAV1 and JAV2, act to disrupt normal S. Typhimurium infection biology and uncovered that they interact with bacterial membrane lipids to help eliminate the bacteria within the host environment. By combining the intrinsic lipophilic and protonatable amine chemical characteristics of these compounds with the innate immunity of the host within the SCV during infection, the molecules act as anti-infectives, are capable of clearing S. Typhimurium from macrophage cells, and prolong the life of S. Typhimurium-infected wax moth larvae.

    This work demonstrates a path for antimicrobial mechanism of action discovery starting from intracellular infection compound screening through animal model infection efficacy testing. Together, data presented demonstrate that JAV1 and JAV2 disrupt bacterial inner membranes by distinct mechanisms and highlight how small, lipophilic, amine-substituted molecules can exploit the host’s innate immunity to facilitate the death of intra-vesicular pathogens. Although these compounds are too toxic to host cells for further antibiotic development, they are an important example of how we can combine our knowledge of bacterial pathophysiology and useful drug characteristics to exploit host-innate immunity to better design molecules that disrupt the host-pathogen interaction. These efforts may help fight against antimicrobial-resistant, intracellular, Gram-negative pathogens.

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  • 2022-07-26
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  • 2024-01-16
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