1st International and 10th National Iranian Conference on Bioinformatics
Home Accepted Papers
How does a bacteriophage enzybiotic target bacteria? Introducing a structural model of bacteriophage PhaxI lytic enzyme
Paper ID : 1093-ICB10
Authors:
Mehri Javid *1, ضرغام سپهری زاده1, احمدرضا شاهوردی1, آزاده ابراهیم حبیبی2
1Department of Pharmaceutical Biotechnology and Pharmaceutical Biotechnology Research Center, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
2Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
Abstract:
Spurred by the emergence and prevalence of multidrug resistance of human pathogens, there has been a global call for novel classes of antibacterials over the last decade. Phages as natural predators of bacteria respond to this call and have been considered a promising candidate since their discovery. Their lytic enzymes serve for cell wall degradation of the infected bacteria. The natural function of these enzymes, also called 'enzybiotics,' can be exploited as powerful enzyme-based antibiotics. These insights have paved the road towards the (pre)clinical development of enzybiotics in various trials phases. Due to poor structural and biochemical characterization, their significant potential as antimicrobials remains unexplored. Verifying structural features and enzymatic specificity is crucial for prospective enzyme modification and further application. Hence, this study aimed to shed light on the 3D structure, determination of essential amino acid residues, and assessment of interactions mode with the bacterial cell wall of a novel PhaxI bacteriophage enzybiotic. A computationally aided method determined that this enzybiotic has two domains: The structure was predicted using the YASARA program and dihedral angles were evaluated by Ramachandran plot with 96.7% residues in the most favored regions. After generating a tautomers library of NAG-NAM-NAG molecules as a piece of the bacterial cell wall, virtual screening was done with Autodock Vina to determine the best substrate-enzyme interaction. The stability and binding affinity of the complex were studied using AMBER 14 forcefield for molecular dynamics simulations for 150 ns (3 × 50 ns) at physiological pH (7.4). The predicted enzyme tunnel and essential residues were further confirmed using Dali server and evolutionary structural relationship studies. These results can subsequently lead to discovering new activities and modes of action of these enzymes to develop potent and more efficient broad-spectrum antibacterials.
Keywords:
Antibiotic resistant; phage lytic enzymes; enzybiotics; homology modeling; molecular dynamic simulation; evolutionary relationships
Status : Paper Accepted (Oral Presentation)