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"Insights into the Development of Predatory Bacteria as a Novel Treatment for Gram-negative Bacterial Infections"

by
Kenneth Shatzkes
Infection, Immunity, and Inflammation (I3) Program
B.Sc. 2009, McGill University, Montréal, QC


Thesis Advisors: Nancy Connell, Ph.D.
Professor, Department of Medicine
and
Daniel Kadouri, Ph.D.
Associate Professor, Department of Oral Biology

Friday, April 21, 2017
2:00 P.M., MBS B-610


Abstract

Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus are predatory bacteria that naturally – and obligately – prey on other Gram-negative bacteria and their use has been proposed as a potential new approach to control microbial infection. The ability of predatory bacteria to prey on Gram-negative human pathogens in vitro is well documented; however, the in vivo safety and efficacy of predatory bacteria have yet to be extensively assessed. In this work, intranasal, intravenous, and intracolonic inoculations were performed to determine the effect of predatory bacteria in mice and rats. Additionally, feces were collected for seven days post-intracolonic inoculation to determine the effect on gut bacterial diversity. No rodent morbidity or abnormal histopathology of the lungs, kidney, liver, or spleen were observed in rodents exposed to predatory bacteria up to 20 days post-inoculation. In all models, a modest increase in pro-inflammatory cytokines (namely TNFá and KC/GRO) was measured within three hours post-inoculation; however, all cytokines but IL-13 within the colon returned to baseline levels by seven days post-inoculation. Furthermore, bacterial dissemination analysis demonstrated that predatory bacteria were efficiently cleared from the host in all models by 20 days post-inoculation. V4 16S rRNA gene sequencing of fecal DNA demonstrated minimal shifts in taxonomic representation in the gut microbiota over the week due to predatory bacteria. Changes in bacterial populations due to exposure to B. bacteriovorus are predicted to contribute to health, however, an overgrowth of Prevotella was observed due to exposure to M. aeruginosavorus. To measure the ability of predatory bacteria to reduce microbial burden in vivo, we introduced sub-lethal concentrations of Klebsiella pneumoniae into either the lungs of rats via intranasal inoculation or the bloodstream via tail vein injection and followed with multiple doses of predatory bacteria over 16-24 hours. Predatory bacteria were unable to significantly reduce K. pneumoniae burden in the blood or prevent dissemination to other organs. In contrast, predatory bacteria were able to reduce K. pneumoniae bacterial burden, on average, by more than 3.0 log10 in the lungs of most rats as measured by CFU plating. The work presented here provides further support for developing predatory bacteria as a novel biocontrol agent.


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