ORCID
https://orcid.org/0000-0002-6067-7705
Date of Award
8-8-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Microorganisms are constantly challenged by stressful environments and have evolved mechanisms to adapt to or counteract these threats. The Gram-negative pathogen Acinetobacter baumannii is thought to rely on a “persist and resist” strategy that facilitates its remarkable ability to survive in a variety of harsh conditions, giving it the capacity to cause life-threatening infections. Currently, over 60% of the global A. baumannii clinical isolates are multidrug resistant (MDR), leading the World Health Organization and the Centers for Disease Control and Prevention to categorize this pathogen as a top priority for the research and development of new antimicrobial therapies. Understanding the mechanisms employed by A. baumannii to sense and respond to stress has a remarkable therapeutic potential, as interfering with these processes may result in novel therapeutic strategies to combat infections. We and others have established that multiple A. baumannii strains respond to a variety of conditions by differentially regulating transcription of the paa operon. The paa operon encodes the enzymes required to degrade phenylacetic acid (PAA), an intermediate in phenylalanine catabolism. PAA displays signaling properties in plants, where it acts as an auxin to regulate multiple cellular processes, however, its role as a potential signaling molecule in bacteria is not well-understood. In this study, we establish that PAA catabolism acts as a regulator of Acinetobacter stress responses. We found that, under subinhibitory concentrations of antibiotics, A. baumannii upregulates expression of the paa operon while simultaneously repressing chaperone-usher Csu pili expression and biofilm formation. The exogenous addition of PAA or its non-metabolizable derivative 4-Fluoro-PAA interferes with this response. Strains unable to modulate PAA levels are less resistant to antibiotics and oxidative stress, have global changes in gene and protein expression, and are attenuated in vivo. To further our understanding of PAA’s role in A. baumannii, we begin to identify key players in the PAA regulatory cascade. Finally, we investigate the potential of repurposing FDA-approved PAA derivative molecules to treat multi-drug resistant A. baumannii.
Language
English (en)
Chair and Committee
Mario Feldman
Recommended Citation
Hooppaw, Anna Josephine, "The Role of Phenylacetic Acid (PAA) Catabolism in Acinetobacter Physiology" (2023). Arts & Sciences Electronic Theses and Dissertations. 3120.
https://openscholarship.wustl.edu/art_sci_etds/3120