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 inhibitorA, in complex withEscherichia coliGyrB24, we expanded the chemical
space of the benzothiazole-based series to the C5 position of the
benzothiazole ring. In particular, compoundEshowed
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-negativeE. coli,Acinetobacter baumannii,Pseudomonas
aeruginosa,andKlebsiella 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.