Dissertation / PhD Thesis

PUBDB-2025-04014

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural and Functional Insightsinto StmPr1: Stenotrophomonasmaltophilia’s Main Virulence Factor

Sommer, M. (Corresponding author)Extern*

2025

Abstract: With the increasing prevalence of antimicrobial resistance (AMR), a pressing globalhealth crisis is emerging, significantly contributing to rising mortality ratesworldwide. The excessive and improper use of antibiotics in both human medicineand agriculture, coupled with insufficient regulation and the global spread ofresistant pathogens, accelerate the development of multidrug-resistant bacteriasuch as Stenotrophomonas maltophilia. This dissertation focuses on the structuraland biochemical characterization of StmPr1, a secreted serine protease involvedin the virulence and persistence of S. maltophilia. Through a combination of X-raycrystallography, small-angle X-ray scattering (SAXS), and molecular dynamics(MD) simulations, the structures of the 36 kDa and 47 kDa forms of StmPr1 wereelucidated. These studies provided key insights into the structural states andcatalytic mechanisms of StmPr1.A major focus of this dissertation was the structural analysis of StmPr1, withparticular attention to differences between the two forms in terms of substratespecificity and binding mode. In addition to the internal differences of StmPr1, theactivity of boronic acid derivatives as potential inhibitors was investigated, as theseare known for their inhibitory effects on serine proteases, particularly asproteasome inhibitors. Furthermore, molecular docking and dynamics simulationswere employed to identify additional potential inhibitors.These bioinformatics findings, in combination with classical structural analyses,shed new light on the role of StmPr1 in the survival and adaptation of S. maltophilia.As such, the results contribute to a better understanding of bacterial proteases aspromising therapeutic targets, particularly in the context of AMR. Moreover, thesuccessful crystallization and subsequent structural characterization using state-17of-the-art methods provide a foundation for future studies, with the potential goalof developing an inhibitor that could aid in the treatment of S. maltophilia infections.By integrating structural bioinformatics, classical X-ray structural analysis, andestablished methods in structural biology and biochemistry, this dissertation laysthe groundwork for a deeper understanding of StmPr1 specifically and bacterialproteases in general. This approach offers a basis for innovative inhibitor designstrategies and is of significant relevance in the fight against infections caused bymultidrug-resistant bacteria.

Note: Dissertation, University of Hamburg, 2025

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)
2. PETRA Beamline P11 (PETRA III)
3. PETRA Beamline P13 (PETRA III)

Appears in the scientific report 2025

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