Characterization of Druggable Genome and Identification of Putative Drug Targets in Multi-drug Resistant Cronobacter Sakazakii

Abstract

Cronobacter Sakazakii is a life threatening multi drug resistant, Gram-negative, human opportunistic and food borne pathogen primarily involved in life threatening meningitis with a mortality rate of 40 to 80% and necrotizing enterocolitis with mortality rate of 10 to 55%, septicemia and bacteremia. Misuse of therapeutic drugs and self-medication along with selection pressure have granted resistivity to pathogen which fuels towards identification of newer and effective drugs. Aim of the study is the identification and characterization of potential drug targets in Cronobacter sakazakii via hierarchical in silico subtractive genomics approach. Qualitative characterization of druggable targets was done by applying various filters for identification of a potential drug target candidate in multiple strains of Cronobacter sakazakii that gives a common target: cell division protein (FtsZ). It is involved in cell cycle-caulobacter pathway which is one of the most promising candidates for drug development. Unavailability of experimentally determined structure homology modeling approach was used to model structure via MODELLER and other web servers. Best modeled structure was selected and used for molecular docking studies. A total of 102 potential inhibitors library with reported activities against FtsZ protein was prepared. The best affinity with the FtsZ was displayed by Compound 78 with GOLD Score of 86. Moreover, time dependent dynamic behavior of docked complex was analyzed using MD simulation studies. MD trajectory analysis revealed the flexibility of loop region to stabilize the binding of ligand and target protein and hydrogen bonding pattern was also rearranged. These conformational changes suggested the potential of 2′′′-hydroxy5′′benzylisouvarinol-B to act as lead compound.