Hit-to-Lead Optimization of Energy-Coupling Factor (ECF) Transporter Inhibitors as Novel Antibiotic

  • J Med Chem. 2026 Jun 25;69(12):14069-14084. doi: 10.1021/acs.jmedchem.5c02721.
Ioulia Exapicheidou  1  2 ,  Aleksei Tsarenko  3 ,  Lena Zeller  1  2 ,  Hamza Ibrahim  1  4 ,  Carole Baumann  1  5 ,  Atanaz Shams  1  2 ,  Patrick A Hoffmann  1  2 ,  Yue Li  4 ,  Andreas M Kany  1  5 ,  Jennifer Hermann  1  5 ,  Dirk J Slotboom  3 ,  Rolf Müller  1  2  5 ,  Andrea Volkamer  1  5  4 ,  Mostafa M Hamed  1  5 ,  Eleonora Diamanti  1  5 ,  Anna K H Hirsch  1  2  5
Affiliations
  • 1. Helmholtz Institute for Pharmaceutical Research (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E 8.1, Saarbrücken, Saarland D-66123, Germany.
  • 2. Saarland University, Department of Pharmacy, Campus E8.1, Saarbrücken, Saarland 66123, Germany.
  • 3. Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, Groningen 9747AG, The Netherlands.
  • 4. Data Driven Drug Design, Center for Bioinformatics, Saarland Informatics Campus, Saarland University, Saarbrücken 66123, Germany.
  • 5. Saarland University, PharmaScienceHub (PSH), Campus E2.1, Saarbrücken 66123, Germany.
PMID: 42249838 DOI: 10.1021/acs.jmedchem.5c02721
Abstract

Multiparameter optimization of a previously identified class of inhibitors of the energy-coupling factor (ECF) transporters enabled the confirmation of in vivo efficacy. ECFs are a class of transmembrane proteins that play a vital role in the active translocation of essential nutrients across cell membranes and are therefore important in the fight against antimicrobial resistance. Aiming to improve the drug-like properties of our inhibitory class, we performed a focused structure-activity relationship study around the Eastern part of our starting molecule 3 by exploiting click chemistry. Our multiparameter optimization resulted in compounds with enhanced metabolic stability and solubility, potent activity against both a panel of Gram-positive bacteria, and against the ECF transporters. We further demonstrate rapid Bacterial killing using Enterococcus faecium as a model organism and confirmed in vivo efficacy of the best compounds in Galleria mellonella larvae and Danio rerio (zebrafish) Infection models, highlighting the therapeutic potential of our approach.

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