A fine-tuned lipophilicity/hydrophilicity ratio governs antibacterial potency and selectivity of bifurcated halogen bond-forming NBTIs

Kolarič, Anja (author), Kokot, Maja (author), Hrast, Martina (author), Weiss, Matjaž (author), Zdovc, Irena (author), Trontelj, Jurij (author), Žakelj, Simon (author), Anderluh, Marko (author), Minovski, Nikola (author)

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
• UDC: 615.4:54
• ISSN on article: 2079-6382
• DOI: 10.3390/antibiotics10070862
• COBISS.SI-ID: 70416899
• Publication date in RUL: 30.03.2022

Record is a part of a journal

• Title: Antibiotics
• Shortened title: Antibiotics
• Publisher: MDPI
• ISSN: 2079-6382
• COBISS.SI-ID: 522975769

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