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PreprintCC BY-NCChemRxiv

Kinetic Target-Guided Discovery of Selective Nanomolar Hydroxamic Acid–Based Inhibitors of Pseudomonas aeruginosa Elastase LasB

  • Virgyl Camberlein1,2,3,4,5
  • Angeliki Vgenopoulou1,4,5
  • Alaa Alhayek1,4,5
  • Roya Shafiei1,4,5
  • Asfandyar Sikandar1
  • Andreas Klein1,4,5
  • Merlin Kempf1
  • Yu-Mi Park1
  • Jelena Konstantinović1
  • Katharina Rox6,1,7,8
  • Andreas M. Kany1,5,8
  • Benoit Deprez2,3
5 more authors
  • Jennifer Herrmann1,4,5,8
  • Rolf Müller1,4,5,8
  • Jörg Haupenthal1,5,8
  • Rebecca Deprez-Poulain2,3
  • Anna K. H. Hirsch1,4,5,8
8 affiliations
  1. 1Helmholtz Centre for Infection Research (HZI
  2. 2Drug Discovery Center
  3. 3U1177, Drugs and Molecules for Living Systems
  4. 4Department of Pharmacy
  5. 5Saarland University
  6. 6Department of Chemical Biology
  7. 7Pharmacokinetics and Pharmacodynamics Unit
  8. 8German Center for Infection Research (DZIF, partner site Hannover-Braunschweig, Braunschweig, Germany, 38124
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Abstract

Antimicrobial resistance is increasingly becoming a critical threat to human health. Pseudomonas aeruginosa is classified as a high-priority pathogen, and treating it with traditional antibiotics is increasingly challenging. In this work, we report on a non-traditional approach: targeting Elastase B, a major virulence factor that drives P. aeruginosa pathogenicity. Guided by prior crystallographic data, we employed a kinetic target-guided synthesis (KTGS) approach followed by an extensive structure–activity relationship (SAR) study, leading to the identification of inhibitors with single-digit nanomolar inhibitory potency (IC50= 1.7 ± 0.1 nM). These compounds also displayed excellent selectivity against a panel of human off-targets, protected lung epithelial cells from LasB-associated damage, and showed encouraging in vivo efficacy. Moreover, pulmonary pharmacokinetic studies revealed ELF and lung exposure above the biochemical IC50 values, supporting their further development as antivirulence agents against P. aeruginosa lung infections.

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Cite

BibTeXRIS
BibTeX
@misc{camberlein2026kinetic,
  title = {{Kinetic Target-Guided Discovery of Selective Nanomolar Hydroxamic Acid–Based Inhibitors of Pseudomonas aeruginosa Elastase LasB}},
  author = {Virgyl Camberlein and Angeliki Vgenopoulou and Alaa Alhayek and Roya Shafiei and Asfandyar Sikandar and Andreas Klein and Merlin Kempf and Yu-Mi Park and Jelena Konstantinović and Katharina Rox and Andreas M. Kany and Benoit Deprez and Jennifer Herrmann and Rolf Müller and Jörg Haupenthal and Rebecca Deprez-Poulain and Anna K. H. Hirsch},
  howpublished = {ChemRxiv},
  year = {2026},
  month = oct,
  doi = {10.26434/chemrxiv.15010074/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010074/v1},
  note = {CC BY-NC},
}
RIS
TY  - UNPB
TI  - Kinetic Target-Guided Discovery of Selective Nanomolar Hydroxamic Acid–Based Inhibitors of Pseudomonas aeruginosa Elastase LasB
AU  - Virgyl Camberlein
AU  - Angeliki Vgenopoulou
AU  - Alaa Alhayek
AU  - Roya Shafiei
AU  - Asfandyar Sikandar
AU  - Andreas Klein
AU  - Merlin Kempf
AU  - Yu-Mi Park
AU  - Jelena Konstantinović
AU  - Katharina Rox
AU  - Andreas M. Kany
AU  - Benoit Deprez
AU  - Jennifer Herrmann
AU  - Rolf Müller
AU  - Jörg Haupenthal
AU  - Rebecca Deprez-Poulain
AU  - Anna K. H. Hirsch
PY  - 2026
DA  - 2026/10/08
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15010074/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010074/v1
AB  - Antimicrobial resistance is increasingly becoming a critical threat to human health. Pseudomonas aeruginosa is classified as a high-priority pathogen, and treating it with traditional antibiotics is increasingly challenging. In this work, we report on a non-traditional approach: targeting Elastase B, a major virulence factor that drives P. aeruginosa pathogenicity. Guided by prior crystallographic data, we employed a kinetic target-guided synthesis (KTGS) approach followed by an extensive structure–activity relationship (SAR) study, leading to the identification of inhibitors with single-digit nanomolar inhibitory potency (IC50= 1.7 ± 0.1 nM). These compounds also displayed excellent selectivity against a panel of human off-targets, protected lung epithelial cells from LasB-associated damage, and showed encouraging in vivo efficacy. Moreover, pulmonary pharmacokinetic studies revealed ELF and lung exposure above the biochemical IC50 values, supporting their further development as antivirulence agents against P. aeruginosa lung infections.
ER  -