2. Academic Validation
  3. Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity

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

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.
PMID: 39303295 DOI: 10.1021/acs.jmedchem.4c01262
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 [Ki (EcLpxC C63A) = 9.5 nM; Ki (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.

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