Development of nanotherapeutics for the treatment of recalcitrant and antibiotic resistant infections

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Peroutka-Bigus, Nathan
Major Professor
Bryan H Bellaire
Committee Member
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Veterinary Microbiology and Preventive Medicine
Our faculty promote the understanding of causes of infectious disease in animals and the mechanisms by which diseases develop at the organismal, cellular and molecular levels. Veterinary microbiology also includes research on the interaction of pathogenic and symbiotic microbes with their hosts and the host response to infection.
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The main focus of this dissertation is on the use of polyanhydride nanoparticles as antimicrobial delivery vehicles to treat the diseases melioidosis caused by the bacterium Burkholderia pseudomallei and primary amoebic meningoencephalitis (PAM) caused by the free-living amoeba Naegleria fowleri.

Melioidosis represents a bacterial disease characterized by antimicrobial resistance, recrudesce, and high mortality. B. pseudomallei is classified as a category B bioterrorism agent as this agent has been studied as a potential bioweapon by various nations. This dissertation shows that these polyanhydride nanoparticles are effective at delivering the antibiotics meropenem, ceftazidime, and chloramphenicol against B. pseudomallei in in vitro broth assays and tissue culture cell models of intracellular pathogenesis.

PAM is a rare disease yet results in a fatal infection with close to 100% mortality with aggressive antimicrobial therapy. Antimicrobials recommended for the treatment of primary amoebic meningoencephalitis were loaded into nanoparticles and screened against N. fowleri in in vitro growth assays. When rifampicin and azithromycin were loaded into these nanoparticles, an improvement in anti-parasitic efficacy was noted.

In summary, these results bolster the effectiveness of polyanhydride nanoparticles as effective drug delivery vehicles across prokaryotic and eukaryotic pathogens.

Additional research discussed is the anti-parasitic activity of the anti-rheumatoid drug auranofin on N. fowleri. In vitro assays found that auranofin has an IC50 of 0.788 µg/mL with the HB-1 strain of N. fowleri. When these amoeba were treated with 3.0 µg/mL auranofin, staining of the nucleus with the cell membrane impermeable dye propidium iodide suggests that auranofin exerts amoebicidal activity. This data suggests that auranofin has potential as a therapy for primary amoebic meningoencephalitis.

Lastly, the impact that the catecholamine hormones norepinephrine and epinephrine have on the replication and antimicrobial susceptibility of Bacillus anthracis and Yersinia pestis. Bacillus anthracis is the causative agent behind the disease anthrax and Y. pestis is the cause of the many manifestation of plague. Norepinephrine was found to accelerate the replication of B. anthracis and render the bacteria less susceptible to the antibiotic rifampicin. While, norepinephrine and epinephrine had the inverse effect with Y. pestis and resulted in a decreased replication rate.

Sat Aug 01 00:00:00 UTC 2020