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.

Computational Design and Development of Benzodioxane-Benzamides as Potent Inhibitors of FtsZ by Exploring the Hydrophobic Subpocket / V. Straniero, V. Sebastián-Pérez, L. Suigo, W. Margolin, A. Casiraghi, M. Hrast, C. Zanotto, I. Zdovc, A. Radaelli, E. Valoti. - In: ANTIBIOTICS. - ISSN 2079-6382. - 10:4(2021), pp. 442.1-442.19.

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

V. Straniero
Co-primo
;
L. Suigo;A. Casiraghi;C. Zanotto;A. Radaelli;E. Valoti
Ultimo
2021

Abstract

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.
Bacillus subtilis; FtsZ; FtsZ inhibition; MIC; MRSA; MSSA; Z ring; antibiotic-resistance; gram positive-dependent diseases
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/19 - Microbiologia Generale
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/839544
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