Outsmarting Biofilms with Protease Triggered Peptide Prodrugs CH-635
Event details
| Date | 31.03.2026 |
| Hour | 16:15 › 17:15 |
| Speaker | Clarissa Melo Czekster |
| Location | |
| Category | Conferences - Seminars |
| Event Language | English |
Abstract :
Up to 80% of bacterial cells live in biofilms, and over 80% of human microbial infections involve biofilm‑associated pathogens, which are often highly resistant to antibiotics. Pseudomonas aeruginosa is a key model for studying chronic biofilm infections due to its remarkable ability to persist for months or years in nutrient‑poor environments. Extracellular proteases and peptidases play central roles in these communities by generating nutrient pools, driving structural remodelling, enabling dispersal, and detoxifying the environment. Many of these enzymes are produced as self-inhibited zymogens that require processing to become active.
By dissecting the molecular mechanisms of protease self‑inhibition, we developed highly selective, tight‑binding inhibitors and chemical probes that target both pre‑formed and newly forming biofilms. Building on this mechanistic understanding, we mapped substrate preferences of key P. aeruginosa proteases and repurposed them as biofilm‑specific activators for an antimicrobial peptide prodrug. Although smart‑release antimicrobial strategies exist, none harness the abundant, biofilm‑specific proteases that dominate chronic infections, and many rely instead on host enzymes which might not always be present. Our protease‑activated peptide prodrug displays a low resistance profile, generating unique resistance mutations not observed in wild‑type strains. Ongoing work is evaluating the fitness of these mutants and exploring synergistic combination strategies.
Biography:
Clarissa Melo Czekster earned her PhD from Albert Einstein College of Medicine (2008-2012), studying mechanisms of enzymes in Mycobacterium tuberculosis, and completed postdoctoral training at Yale University (2012-2014) and at the University of St Andrews. In 2018, she established her independent research group with a prestigious Wellcome trust Sir Henry Dale fellowship. Czekster is currently a Reader in the School of Biology at the University of St Andrews, where she leads interdisciplinary research in enzymology, structural biology, microbiology and chemical biology. Her research focuses on developing novel antimicrobial and antibiofilm compounds, engineering microbial natural product biosynthesis for biocatalysis, and applying enzyme engineering to produce novel molecules. Additional areas include the synthesis of unprecedented and isotopically labelled nucleosides and nucleotides, as well as peptide-based antimicrobials. Her group has established technologies enabling the production of antibiofilm peptides and nucleotides from simple, inexpensive precursors in a single step.
Website:
https://czeksterlab.wp.st-andrews.ac.uk/
Up to 80% of bacterial cells live in biofilms, and over 80% of human microbial infections involve biofilm‑associated pathogens, which are often highly resistant to antibiotics. Pseudomonas aeruginosa is a key model for studying chronic biofilm infections due to its remarkable ability to persist for months or years in nutrient‑poor environments. Extracellular proteases and peptidases play central roles in these communities by generating nutrient pools, driving structural remodelling, enabling dispersal, and detoxifying the environment. Many of these enzymes are produced as self-inhibited zymogens that require processing to become active.
By dissecting the molecular mechanisms of protease self‑inhibition, we developed highly selective, tight‑binding inhibitors and chemical probes that target both pre‑formed and newly forming biofilms. Building on this mechanistic understanding, we mapped substrate preferences of key P. aeruginosa proteases and repurposed them as biofilm‑specific activators for an antimicrobial peptide prodrug. Although smart‑release antimicrobial strategies exist, none harness the abundant, biofilm‑specific proteases that dominate chronic infections, and many rely instead on host enzymes which might not always be present. Our protease‑activated peptide prodrug displays a low resistance profile, generating unique resistance mutations not observed in wild‑type strains. Ongoing work is evaluating the fitness of these mutants and exploring synergistic combination strategies.
Biography:
Clarissa Melo Czekster earned her PhD from Albert Einstein College of Medicine (2008-2012), studying mechanisms of enzymes in Mycobacterium tuberculosis, and completed postdoctoral training at Yale University (2012-2014) and at the University of St Andrews. In 2018, she established her independent research group with a prestigious Wellcome trust Sir Henry Dale fellowship. Czekster is currently a Reader in the School of Biology at the University of St Andrews, where she leads interdisciplinary research in enzymology, structural biology, microbiology and chemical biology. Her research focuses on developing novel antimicrobial and antibiofilm compounds, engineering microbial natural product biosynthesis for biocatalysis, and applying enzyme engineering to produce novel molecules. Additional areas include the synthesis of unprecedented and isotopically labelled nucleosides and nucleotides, as well as peptide-based antimicrobials. Her group has established technologies enabling the production of antibiofilm peptides and nucleotides from simple, inexpensive precursors in a single step.
Website:
https://czeksterlab.wp.st-andrews.ac.uk/
Practical information
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- Free