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Dissertation Seminar – Lauren Radlinski
February 28, 2020 @ 3:30 pm - 4:30 pm
Lauren Radlinski
“Harnessing interspecies antagonism to enhance antibiotic efficacy.”
Friday, February 28, 2020
3:30 p.m.
1131 Bioinformatics
Dissertation Advisor: Dr. Brian Conlon
Presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy
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Lauren Radlinski
Abstract
Beyond genetically encoded mechanisms of resistance, the factors that contribute to antibiotic treatment failure within the host are poorly understood. Traditional susceptibility assays fail to account for extrinsic determinants of antibiotic susceptibility present during infection and are therefore poor predictors of treatment outcome. To maximize the reach of current therapeutics, we must develop a more sophisticated understanding of antibiotic efficacy in the infection environment. Here we demonstrate that interspecies interactions between two important opportunistic pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, alters S. aureus response to antibiotics. We show that the P. aeruginosa-produced endopeptidase LasA potentiates lysis of S. aureus by vancomycin, rhamnolipids facilitate proton-motive force-independent aminoglycoside uptake, and that small molecule 4-hydroxy-2-heptylquinoline-N-oxide (HQNO) induces multidrug tolerance in S. aureus through respiratory inhibition and reduction of cellular ATP. We further demonstrate rhamnolipid-mediated potentiation of aminoglycoside uptake and killing of S. aureus restores susceptibility to otherwise tolerant persister, biofilm, small colony variant, anaerobic, and resistant S. aureus populations.
Furthermore, bacterial pathogens that replicate within the intracellular niche are protected from antibiotics that cannot penetrate the eukaryotic membrane. Identifying and disrupting the pathways used by these pathogens to modify the intracellular niche in order to survive is an alternative strategy for limiting bacterial proliferation. Here, we use Francisella tularensis as a model intracellular bacterial pathogen to identify and describe the bacterial metabolic pathways and host-derived nutrients necessary for intracellular and in vivo growth. These findings reveal potential new therapeutic strategies for disrupting bacterial nutrient acquisition that may be broadly applicable for treating other important intracellular pathogens.
Overall, the findings presented here suggest that antibiotic susceptibility is contingent on a multitude of factors including interspecies interaction and the physiological replicative niche. Further elucidation of key antibiotic susceptibility determinants in vivo, as well as of strategies to overcome barriers to antibiotic efficacy may lead to a more holistic and personalized approach to therapy that will aid in the resolution of persistent infection.
