Hijacking Anaerobic Metabolism to Restore Antibiotic Efficacy in Pseudomonas aeruginosa
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Date
2024
Authors
Gentry-Lear, Zealon
Journal Title
Journal ISSN
Volume Title
Publisher
University of Oregon
Abstract
Aggressive antibiotic treatment often fails to resolve chronic infections. Most antibiotics target fast-growing bacteria, however, pathogens like Pseudomonas aeruginosa grow slowly in chronic infection environments because of oxygen limitation (hypoxia). Thus, antibiotic treatment failure occurs in oxygen limited (hypoxic) environments when slow bacterial growth facilitates tolerance to antibiotics or because many bacteria are resistant to antibiotics. The goal of this thesis is to identify new therapeutic strategies to kill pathogens under hypoxic conditions like those in chronic infections. Chlorate is a drug that kills P. aeruginosa growing in conditions with no oxygen by hijacking a metabolic process known as nitrate respiration. This pathway converts nontoxic chlorate into toxic chlorite, which kills P. aeruginosa. Chlorate and antibiotic treatment are most effective against P. aeruginosa growing in low oxygen and high oxygen conditions, respectively, but neither is effective at killing P. aeruginosa cells under hypoxic conditions. We found that chlorate interacts synergistically with different classes of antibiotics to eliminate hypoxic P. aeruginosa populations, overcoming both antibiotic tolerance and resistance. Chlorate has a unique ability to synergize with different classes of drugs because most antibiotic-antibiotic combinations did not display synergy. Future work will focus on understanding the mechanism of chlorate-antibiotic synergy and why antibiotic-antibiotic combinations are not synergistic. Identifying synergistic drug combinations holds promise for curing recalcitrant infections, where current antibiotic-only treatments often fail patients. This thesis includes co-authored material and collaboratively produced work.
Description
49 pages
Keywords
Biology, Bacteria, Antibiotics, Microbiology, Infections