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

Kokot, Maja (author), Weiss, Matjaž (author), Zdovc, Irena (author), Šenerović, Lidija (author), Radakovic, Natasa (author), Anderluh, Marko (author), Minovski, Nikola (author), Hrast, Martina (author)

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.

• Language: English
• Keywords: NBTIs, DNA gyrase, topoisomerase IV, antibacterials, MRSA, hERG inhibition, in vivo efficacy
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; VF - Veterinary Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 13 str.
• Numbering: Vol. 250, art. 115160
• PID: 20.500.12556/RUL-144295
• UDC: 615.28
• ISSN on article: 0223-5234
• DOI: 10.1016/j.ejmech.2023.115160
• COBISS.SI-ID: 141418755
• Publication date in RUL: 13.02.2023

Record is a part of a journal

• Title: European journal of medicinal chemistry
• Shortened title: Eur. j. med. chem.
• Publisher: Elsevier
• ISSN: 0223-5234
• COBISS.SI-ID: 25429760

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: DNA giraza, topoizomeraza IV, antibakterijska zdravila, inhibicija, učinkovitost in vivo, farmacevtska kemija, bakterije