Computational Approach For Analyzing Resistance In Staphylococcus Aureus Against Aztreonam And Ceftazidime Contrasting Nonresistance Β-Lactam Antibiotics

Abstract

The contemporary landscape of drug design is witnessing a pronounced shift towards the utilization of dry lab, predominantly owing to the availability of robust and reliable software tools, coupled with the convenience of computational work. The primary objective of this study is to validate the efficacy of the in Silico (dry lab) approach for subsequent In vitro analysis. Our focus is to establish a correlation between the results obtained through the Antimicrobial Susceptibility Test (AST) using the disc diffusion method and the docking scores of, β-lactam and all drugs representing these antibiotic classes are known to interact with the same receptor, Penicillin-binding Protein (PBP).

To achieve this, we employed six different docking software tools, each utilizing distinct approaches for ligand-receptor interactions. These tools include Autodock Vina 4, Swissdock, Discovery Studio (CD Docker) for site-specific ligand binding to receptors, CB dock2 for blind docking, and Protein Plus and Patchdock, which are pocket-cavity-based docking algorithms. The results of our analysis reveal varying degrees of correlation between the docking scores and the AST results. Notably, a significant positive association was observed in Swissdock, followed by Discovery Studio (CD Docker), while Autodock Vina 4 demonstrated only a moderate association. The significance levels, as determined by p-values, were consistently below 0.05 in these instances.

In conclusion, our study underscores the necessity for standardization and harmonization among different docking software to ensure consistency in results. To enhance validation, we conducted molecular dynamics simulations spanning 100 nanoseconds each. This extensive timeframe allows for   effective ligand-protein stabilization.MD simulation reveals RMSD value of ceftazidime (0.000493- 14.337) was the lowest among all β-lactam that’s in agreement with In vitro results ceftazidime have zone of inhibition (zoi) nil. The RMSF value of aztreonam was (0.0562-0.8636) highest among all β-lactam, higher RMSF values suggest greater flexibility and possibly less stability in specific parts of the molecule. which matches with In vitro result zoi of aztreonam was nil.