Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity
In a fragment-based approach using NMR spectroscopy, benzyloxyacetohydroxamic acid-derived inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the uridine diphosphate-binding site of the enzyme were developed. By appending privileged fragments via a suitable linker, potent LpxC inhibitors with promising antibacterial activities could be obtained, like the one-digit nanomolar LpxC inhibitor (<i>S</i>)-<b>13j</b> [<i>K</i><sub><i>i</i></sub> (<i>Ec</i>LpxC C63A) = 9.5 nM; <i>K</i><sub><i>i</i></sub> (<i>Pa</i>LpxC): 5.6 nM]. To rationalize the observed structure-activity relationships, molecular docking and molecular dynamics studies were performed. Initial in vitro absorption-distribution-metabolism-excretion-toxicity (ADMET) studies of the most potent compounds have paved the way for multiparameter optimization of our newly developed isoserine-based amides.
Authors
- Maria Riedner (ORCID: https://orcid.org/0000-0003-4421-998X)
- Katharina J. Hoff (ORCID: https://orcid.org/0000-0002-7333-8390)
- Holger Rohde
- Isabelle Krimm (ORCID: https://orcid.org/0000-0002-5981-109X)
- Katharina Rox (ORCID: https://orcid.org/0000-0002-8020-1384)
- Fady Baselious (ORCID: https://orcid.org/0000-0003-3242-8514)
- Andreas M. Kany (ORCID: https://orcid.org/0000-0001-7580-3658)
- Wolfgang Sippl (ORCID: https://orcid.org/0000-0002-5985-9261)
- Ralph Holl (ORCID: https://orcid.org/0000-0001-8511-3546)
- Jörg Haupenthal (ORCID: https://orcid.org/0000-0003-3991-2800)
- Sebastian Mielniczuk
- Anna K. H. Hirsch (ORCID: https://orcid.org/0000-0001-8734-4663)
- Yunqi Li (ORCID: https://orcid.org/0000-0002-2841-1253)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Universität Hamburg (DE)
- Centre Léon Bérard (FR)
- University Medical Center Hamburg-Eppendorf (DE)
- German Center for Infection Research (DE)
- Helmholtz Centre for Infection Research (DE)
- Centre de Recherche en Cancérologie de Lyon (FR)
- Helmholtz Center for Information Security (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- East China Normal University (CN)
- Martin Luther University Halle-Wittenberg (DE)
- Saarland University (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01262
- Citations
- 5
- Primary Topic
- Peptidase Inhibition and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.41
Funders
- Deutsches Zentrum für Infektionsforschung
- Deutsche Forschungsgemeinschaft