Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity PMID: 39303295

GLP-1 and Obesity Research

2026-08-18

Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity

J Med Chem. 2024 Oct 10;67(19):17363-17391. doi: 10.1021/acs.jmedchem.4c01262.

Sebastian Mielniczuk ¹ ² , Katharina Hoff ¹ ² , Fady Baselious ³ , Yunqi Li ⁴ ⁵ , Jörg Haupenthal ⁶ , Andreas M Kany ⁶ , Maria Riedner ⁷ , Holger Rohde ² ⁸ , Katharina Rox ⁹ ¹⁰ , Anna K H Hirsch ⁶ ¹¹ ¹² , Isabelle Krimm ⁴ , Wolfgang Sippl ³ , Ralph Holl ¹ ²

Affiliations

1. Institute of Organic Chemistry, Universität Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
2. German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, 20146 Hamburg, Germany.
3. Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, Kurt-Mothes-Straße 3, 06120 Halle (Saale), Germany.
4. Team "Small Molecules for Biological Targets", Institut Convergence Plascan, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, 69008 Lyon, France.
5. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences & School of Life Sciences, East China Normal University, 200241 Shanghai, China.
6. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123 Saarbrücken, Germany.
7. Technology Platform Mass Spectrometry, Universität Hamburg, Mittelweg 177, 20148 Hamburg, Germany.
8. Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
9. Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstr. 7, 38124 Braunschweig, Germany.
10. German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 38124 Braunschweig, Germany.
11. Helmholtz International Lab for Anti-infectives, Campus E8.1, 66123 Saarbrücken, Germany.
12. Department of Pharmacy, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany.

Abstract

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 (S)-13j [K_i (EcLpxC C63A) = 9.5 nM; K_i (PaLpxC): 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.