Maša Sterle (Author), Martina Durcik (Author), Clare E. M. Stevenson (Author), Sara R. Henderson (Author), Petra Eva Szili (Author), Marton Czikkely (Author), David M. Lawson (Author), Danijel Kikelj (Author), Nace Zidar (Author), Lucija Peterlin-Mašič (Author), Janez Ilaš (Author), Tihomir Tomašić (Author), Andrej Emanuel Cotman (Author), Anamarija Zega (Author)

Abstract

We present a new series of 2-aminobenzothiazole-based DNA gyrase B inhibitors with promising activity against ESKAPE bacterial pathogens. Based on the binding information extracted from the cocrystal structure of DNA gyrase B inhibitor A, in complex with Escherichia coli GyrB24, we expanded the chemical space of the benzothiazole-based series to the C5 position of the benzothiazole ring. In particular, compound E showed low nanomolar inhibition of DNA gyrase (IC50 < 10 nM) and broad-spectrum antibacterial activity against pathogens belonging to the ESKAPE group, with the minimum inhibitory concentration < 0.03 μg/mL for most Gram-positive strains and 4–16 μg/mL against Gram-negative E. coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. To understand the binding mode of the synthesized inhibitors, a combination of docking calculations, molecular dynamics (MD) simulations, and MD-derived structure-based pharmacophore modeling was performed. The computational analysis has revealed that the substitution at position C5 can be used to modify the physicochemical properties and antibacterial spectrum and enhance the inhibitory potency of the compounds. Additionally, a discussion of challenges associated with the synthesis of 5-substituted 2-aminobenzothiazoles is presented.

Keywords

inhibitorji;organske kisline;proteini;bacteria;genetics;inhibitors;organic acids;peptides;proteins;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 579.8:615.2
COBISS: 157232131 Link will open in a new window
ISSN: 2470-1343
Views: 18
Downloads: 4
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Other data

Secondary language: Slovenian
Secondary keywords: Bakterije;Genetika;Peptidi;
Type (COBISS): Article
Pages: str. 24387-24395
Volume: ǂVol. ǂ8
Issue: ǂiss. ǂ27
Chronology: 2023
DOI: 10.1021/acsomega.3c01930
ID: 21372097