Computational Design and Development of Benzodioxane-Benzamides as Potent Inhibitors of FtsZ by Exploring the Hydrophobic Subpocket

Multidrug resistant 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 potentia...

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Bibliographic Details
Published in:Antibiotics (Basel) 2021-04, Vol.10 (4), p.442
Main Authors: Straniero, Valentina, Sebastián-Pérez, Victor, Suigo, Lorenzo, Margolin, William, Casiraghi, Andrea, Hrast, Martina, Zanotto, Carlo, Zdovc, Irena, Radaelli, Antonia, Valoti, Ermanno
Format: Article
Language:English
Subjects:
Antibiotic resistance
Antibiotics
Antimicrobial agents
Bacillus subtilis
Benzamide
Binding sites
Cell division
Chemical properties
Computer applications
Design
Drug resistance
Fluorescence
Fluorescence microscopy
FtsZ
gram positive-dependent diseases
Hydrogen bonds
Hydrophobicity
Inhibitors
Localization
Methicillin
MRSA
MSSA
Multidrug resistance
Nosocomial infection
Pathogens
Penicillin
Permeability
Proteins
Staphylococcus aureus
Staphylococcus infections
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Summary:Multidrug resistant 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 , as well as another Gram positive species, 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.
ISSN:2079-6382
2079-6382
DOI:10.3390/antibiotics10040442