Trial Lecture and Thesis Defense - Daniel Salamonsen

Master of Science Daniel Salamonsen will hold the Trial Lecture and Thesis Defense for the PhD degree in Science on Friday, October 16, 2026.

Trial Lecture

Takes place 10:15 - 11:15.

The title of the Trial Lecture is:

« Combination Therapies for Bacterial Pathogens: Rationale, Evidence, and Future Directions from lab to the clinic »

Thesis Defense

Takes place 12:15 - 15:00.

The title of the thesis is:

« β-lactamases: From trade-offs and adaptability to inhibitor design. The roles of collateral sensitivity, epistasis, and conformational dynamics in resistance evolution »

Abstract

β-lactamases are widespread bacterial enzymes that can rapidly adapt to new β-lactam antibiotics and are therefore major drivers of antibiotic resistance. This thesis investigates how β-lactamase evolution is shaped by conformational dynamics and biological trade-offs, including collateral sensitivity, whereby increased resistance to one drug results in increased susceptibility to another.

Using the class D β-lactamase OXA-48 as a model, the work showed that adaptation to the cephalosporin ceftazidime, which the enzyme normally hydrolyses poorly, caused strong collateral sensitivity to its native substrates piperacillin and meropenem. The mutation F72L was central to these trade-offs by altering the flexibility of loops surrounding the active site and the distribution between functional conformations. Increased Ω-loop flexibility impaired productive piperacillin binding, whereas reduced meropenem activity resulted from a shift toward a conformation less favourable for hydrolysis. Co-selection with piperacillin and ceftazidime promoted the mutation V120G, which partially restored piperacillin resistance without substantially reducing ceftazidime resistance, probably by stabilizing the Ω-loop. This effect depended on F72L, demonstrating that strong collateral sensitivity can be weakened through further evolution. The results also show that conformational dynamics can both promote resistance and impose functional constraints, providing a rationale for incorporating dynamic principles into inhibitor design.

Building on this perspective, the thesis examined stereodynamically chiral phosphonic acids as inhibitors of the metallo-β-lactamases NDM-1, VIM-2, and GIM-1. Their interconverting stereoisomers adopted distinct binding modes, providing adaptability across different enzymes and potentially greater tolerance to resistance-conferring mutations.

Overall, the findings support a dynamic view of β-lactamase evolution, in which structural and conformational changes can both generate resistance and reveal exploitable biological vulnerabilities. Identifying general evolutionary principles may improve resistance prediction and support the development of more robust inhibitors and treatment strategies.

Supervisory Committee

• Associate Professor Christopher Frøhlich, Department of Medical Biology, UiT (Main Supervisor)
• Professor Hanna-Kirsti Schrøder Leiros, Department of Chemistry, UiT
• Professor Rafi Ahmad, Inland Norway University of Applied Sciences, Lillehammer, Norway 

Evaluation Committee

• 1st Opponent: Reader Dr. Clarissa Melo Czekster, School of Biology, University of St Andrews, United Kingdom
• 2nd Opponent: Professor Daniel E. Rozen, Institute of Biology Leiden (IBL), Leiden University, Netherlands
• Internal member and leader of the committee: Researcher Edda Marie Rainer, Department of Chemistry, UiT, Norway

Streaming

The Trial Lecture and Thesis Defense will be streamed via Panopto:

Trial Lecture (10:15 - 11:15)
Watch the Trial Lecture

Thesis Defense (12:15 - 15:00)
Watch the Thesis Defense

Thesis

The thesis is available in Munin:

View the thesis in Munin