Computational design and development of benzodioxane-benzamides as potent inhibitors of FtsZ by exploring the hydrophobic subpocket
ID Straniero, Valentina (Author), ID Sebastián-Pérez, Victor (Author), ID Suigo, Lorenzo (Author), ID Margolin, William (Author), ID Casiraghi, Andrea (Author), ID Hrast, Martina (Author), ID Zanotto, Carlo (Author), ID Zdovc, Irena (Author), ID Radaelli, Antonia (Author), ID Valoti, Ermanno (Author)

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Multidrug resistant Staphylococcus aureus is a severe threat, responsible for most of the nosocomial infections globally. This resistant strain is associated with a 64% increase in death compared to the antibiotic-susceptible strain. The prokaryotic protein FtsZ and the cell division cycle have been validated as potential targets to exploit in the general battle against antibiotic resistance. Despite the discovery and development of several anti-FtsZ compounds, no FtsZ inhibitors are currently used in therapy. This work further develops benzodioxane-benzamide FtsZ inhibitors. We seek to find more potent compounds using computational studies, with encouraging predicted drug-like profiles. We report the synthesis and the characterization of novel promising derivatives that exhibit very low MICs towards both methicillin-susceptible and -resistant S. aureus, as well as another Gram positive species, Bacillus subtilis, while possessing good predicted physical-chemical properties in terms of solubility, permeability, and chemical and physical stability. In addition, we demonstrate by fluorescence microscopy that Z ring formation and FtsZ localization are strongly perturbed by our derivatives, thus validating the target.

Keywords:gram positive-dependent diseases, antibiotic-resistance, MSSA, MRSA, Bacillus subtilis, FtsZ, Z ring, FtsZ inhibition, MIC, pharmacology, chemistry, anti-bacterial agents, methicillin-resistant Staphylococcus aureus, drug resistance, microbiology, benzamides, bacterial proteins
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
Number of pages:19 str.
Numbering:Vol. 10, iss. 4, art. 442
PID:20.500.12556/RUL-135340 This link opens in a new window
ISSN on article:2079-6382
DOI:10.3390/antibiotics10040442 This link opens in a new window
COBISS.SI-ID:59812611 This link opens in a new window
Publication date in RUL:08.03.2022
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Shortened title:Antibiotics
COBISS.SI-ID:522975769 This link opens in a new window


License:CC BY 4.0, Creative Commons Attribution 4.0 International
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:15.04.2021

Secondary language

Keywords:veterinarska medicina


Funder:NIH - National Institutes of Health
Project number:GM131705

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