Inhibition of seryl tRNA synthetase by seryl nucleoside moiety (SB-217452) of albomycin antibiotic.

The seryl nucleoside moiety (SB-217452) of the Trojan horse antibiotic albomycin exhibits broad spectrum antibiotic activity against various bacterial pathogens by targeting seryl tRNA synthetase (SerRS). The aim of the present study is to understand how the SB-217452 inhibits SerRSs of different species. First, the binding efficacy of SB-217452 in the dimeric SerRS from Thermus thermophilus (TtSerRS) in complex with tRNASer is compared with the binding of seryl adenylate (Ser-AMP). Multiple reasons for inhibition action of SB-217452 are revealed. In the next part, we have compared the binding event of SB-217452 in SerRS from Staphylococcus aureus (SaSerRS) and from Streptomyces sp. (SpSerRS1). First, quantum mechanical study (AIM analysis) shows that the network of interaction is stronger in SaSerRS:tRNA complex compared to the SpSerRS1:tRNA complex. This conclusion is in fair agreement with the observed IC50 values which show that the binding free energy of SB-217452 in the active site of SaSerRS is more favorable compared to that in SpSerRS1. The interactions of antibiotic with ß sheets contribute to the differences in the binding behavior. Secondly, the classical simulation results corroborate the results of AIM analysis. Finally, metadynamics calculation of the free energy surface of the conformational change of the SB-217452 shows that the antibiotic binds in a unique catalytically non competent organization in SaSerRS:tRNA. In contrast, the antibiotic can bind in the active site of SpSerRS1:tRNA complex with multiple catalytically incompetent conformations. The present study provides a comprehensive molecular perspective of the inhibition mechanism of the antibiotic.Communicated by Ramaswamy H. Sarma.