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Free keywords:
phage therapy; antibiotic resistance; evolution; microbial resistance
Abstract:
The rise of antibiotic resistant bacteria is a global threat to public health and food security. Bacteriophages (phages) - viruses that kill and infect bacteria - are a promising alternative. Bacteriophages have successfully treated antibiotic resistant infections. However, as with antibiotics, phage resistance can also evolve.
Bacteriophages attach to molecules on the bacterial outer membrane to infect the cell, e.g., lipopolysaccharides (LPS). A mutation in bacteria that modifies this surface molecule often leads to phage resistance. In this thesis, we study the mechanism of phage resistance evolution by surface modifications, using 30 Escherichia coli C LPS mutants resistant to ΦX174, an LPS-targeting phage (Chapter 3). We first evolved phages that can infect each of these initially resistant mutants. Some types of resistance are harder to overcome than others. I also investigated how LPS changes influence cell shape.
LPS modifications can also impact antibiotic susceptibility, allowing for phage-antibiotic synergism. I measured susceptibility of LPS mutants to two antibiotics (Chapter 4). We find that deep rough mutants have increased chloramphenicol susceptibility but not gentamicin susceptibility. Hypothesis testing shows that treating E. coli C wildtype with ΦX174 and chloramphenicol eliminates deep rough mutants, and reduces phage resistance evolution. Our results illustrate the mechanism for phage-antibiotic synergism in our model system.
In Chapter 5, I investigated the molecular basis of altered antibiotic susceptibility in cell surface mutants. Finally, I studied effects of phage adaptation to host before treatment (Chapter 6).
This thesis provides a framework to understand the evolutionary consequences of phage resistance. The insights can help design evolution-informed treatments with reduced phage resistance evolution.
