Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens

Sterle, Masa and Durcik, Martina and Stevenson, Clare E. M. and Henderson, Sara R. and Szili, Petra and Czikkely, Márton Simon and Pál, Csaba (2023) Exploring the 5-Substituted 2-Aminobenzothiazole-Based DNA Gyrase B Inhibitors Active against ESKAPE Pathogens. ACS OMEGA, 8. pp. 24387-24395. ISSN 2470-1343

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Abstract

We present a new series of 2-aminobenzothiazole-basedDNA gyraseB inhibitors with promising activity against ESKAPE bacterial pathogens.Based on the binding information extracted from the cocrystal structureof DNA gyrase B inhibitor A, in complex with Escherichia coli GyrB24, we expanded the chemicalspace of the benzothiazole-based series to the C5 position of thebenzothiazole ring. In particular, compound E showedlow nanomolar inhibition of DNA gyrase (IC50 < 10 nM)and broad-spectrum antibacterial activity against pathogens belongingto the ESKAPE group, with the minimum inhibitory concentration <0.03 & mu;g/mL for most Gram-positive strains and 4-16 & mu;g/mLagainst Gram-negative E. coli, Acinetobacter baumannii, Pseudomonasaeruginosa, and Klebsiella pneumoniae. To understand the binding mode of the synthesized inhibitors, acombination 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 positionC5 can be used to modify the physicochemical properties and antibacterialspectrum and enhance the inhibitory potency of the compounds. Additionally,a discussion of challenges associated with the synthesis of 5-substituted2-aminobenzothiazoles is presented.

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