Maja Kokot (Author), Matjaž Weiss (Author), Irena Zdovc (Author), L. Šenerović (Author), Natasa Radakovic (Author), Marko Anderluh (Author), Nikola Minovski (Author), Martina Hrast (Author)

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

DNA giraza;topoizomeraza IV;antibakterijska zdravila;inhibicija;učinkovitost in vivo;NBTIs;DNA gyrase;Topoisomerase IV;antibacterials;MRSA;hERG inhibition;in vivo efficacy;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.28
COBISS: 141418755 Link will open in a new window
ISSN: 0223-5234
Views: 255
Downloads: 31
Average score: 0 (0 votes)
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Other data

Secondary language: Slovenian
Secondary keywords: Bakterije;Farmacevtska kemija;
Type (COBISS): Article
Pages: str. 1-13
Issue: ǂVol. ǂ250
Chronology: 2023
DOI: 10.1016/j.ejmech.2023.115160
ID: 17994510