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A fine-tuned lipophilicity/hydrophilicity ratio governs antibacterial potency and selectivity of bifurcated halogen bond-forming NBTIs
ID Kolarič, Anja (Author), ID Kokot, Maja (Author), ID Hrast, Martina (Author), ID Weiss, Matjaž (Author), ID Zdovc, Irena (Author), ID Trontelj, Jurij (Author), ID Žakelj, Simon (Author), ID Anderluh, Marko (Author), ID Minovski, Nikola (Author)

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Abstract
Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against some of the most concerning hard-to-treat pathogens for which new antibacterials are urgently needed, as reported by the WHO and CDC. NBTIs enzyme activity and whole cell potency seems to depend on the fine-tuned lipophilicity/hydrophilicity ratio that governs the permeability of those compounds through the bacterial membranes. Lipophilicity of NBTIs is apparently optimal for passing through the membrane of Gram-positive bacteria, but the higher, although not excessive lipophilicity and suitable hydrophilicity seems to determine the passage through Gram-negative bacterial membranes. However, due to the considerable hERG inhibition, which is still at least two orders of magnitude away from MICs, continued optimization is required to realize their full potential.

Language:English
Keywords:antibacterials, drug discovery, DNA gyrase inhibitors, topoisomerase IV inhibitors, intercalators, novel bacterial topoisomerase inhibitors, topoisomerase II inhibitors, intercalating agents
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:2021
Number of pages:30 str.
Numbering:Vol. 10, iss. 7, art. 862
PID:20.500.12556/RUL-135734 This link opens in a new window
UDC:615.4:54
ISSN on article:2079-6382
DOI:10.3390/antibiotics10070862 This link opens in a new window
COBISS.SI-ID:70416899 This link opens in a new window
Publication date in RUL:30.03.2022
Views:1141
Downloads:134
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Record is a part of a journal

Title:Antibiotics
Shortened title:Antibiotics
Publisher:MDPI
ISSN:2079-6382
COBISS.SI-ID:522975769 This link opens in a new window

Licences

License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:15.07.2021

Secondary language

Language:Slovenian
Keywords:farmacevtska kemija, antibakterijska sredstva, raziskave zdravil, zaviralci DNA giraz, zaviralci topoizomeraze IV, interkalator, novi zaviralci bakterijske topoizomeraze

Projects

Funder:ARRS - Slovenian Research Agency
Project number:P1-0017
Name:Modeliranje kemijskih procesov in lastnosti spojin

Funder:ARRS - Slovenian Research Agency
Project number:P1-0208
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

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