Computational design and development of benzodioxane-benzamides as potent inhibitors of FtsZ by exploring the hydrophobic subpocket
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.
2021
2022-03-08 12:01:37
1033
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
veterinarska medicina
dk_c
Valentina
Straniero
70
Victor
Sebastián-Pérez
70
Lorenzo
Suigo
70
William
Margolin
70
Andrea
Casiraghi
70
Martina
Hrast
70
Carlo
Zanotto
70
Irena
Zdovc
70
Antonia
Radaelli
70
Ermanno
Valoti
70
UDK
4
579:615.2:57.08
ISSN pri članku
9
2079-6382
DOI
15
10.3390/antibiotics10040442
COBISS_ID
3
59812611
RAZ_Straniero_Valentina_2021.pdf
5758167
Predstavitvena datoteka
2022-03-08 12:03:21
0
Izvorni URL
2022-03-08 12:01:39