2. Academic Validation
  3. Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy

Amide containing NBTI antibacterials with reduced hERG inhibition, retained antimicrobial activity against gram-positive bacteria and in vivo efficacy

  • Eur J Med Chem. 2023 Mar 15;250:115160. doi: 10.1016/j.ejmech.2023.115160.
Maja Kokot 1,  Matjaž Weiss 2,  Irena Zdovc 3,  Lidija Senerovic 4,  Natasa Radakovic 4,  Marko Anderluh 2,  Nikola Minovski 5,  Martina Hrast 6
Affiliations

Affiliations

  • 1 Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000, Ljubljana, Slovenia.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000, Ljubljana, Slovenia.
  • 3 Institute of Microbiology and Parasitology, Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000, Ljubljana, Slovenia.
  • 4 Laboratory for Microbial Molecular Genetics and Ecology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11 042, Belgrade, Serbia.
  • 5 Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia. Electronic address: [email protected].
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva Cesta 7, 1000, Ljubljana, Slovenia. Electronic address: [email protected].
PMID: 36753879 DOI: 10.1016/j.ejmech.2023.115160
Abstract

Novel bacterial Topoisomerase inhibitors (NBTIs) are new promising antimicrobials for the treatment of multidrug-resistant Bacterial infections. In recent years, many new NBTIs have been discovered, however most of them struggle with the same issue - the balance between Antibacterial activity and hERG-related toxicity. We started a new campaign by optimizing the previous series of NBTIs, followed by the design and synthesis of a new, amide-containing focused NBTI library to reduce hERG inhibition and maintain Antibacterial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This optimization strategy yielded the lead compound 12 that exhibits potent Antibacterial activity against Gram-positive bacteria, reduced hERG inhibition, no cardiotoxicity in zebrafish model, and a favorable in vivo efficacy in a neutropenic murine thigh Infection model of MRSA Infection.

Keywords

Antibacterials; DNA gyrase; In vivo efficacy; MRSA; NBTIs; Topoisomerase IV; hERG inhibition.

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