Empowering Therapeutic Strategies against Methicillin-Resistant Staphylococcus Aureus Riboswitch: Unveiling the Potential of Small Molecules and Antisense Oligonucleotides through In Silico Analysis

Methicillin-resistant Staphylococcus aureus (MRSA) poses an increasingly alarming threat to global public health, characterized by its escalating antibiotic resistance and heightened virulence. This dire situation necessitates the exploration of novel and hitherto uncharted targets for effective pathogen control. The primary objective of our current investigation is to identify the most promising riboswitch as a druggable target and assess its potential inhibition through both small molecules and antisense oligonucleotides (ASO) in silico. I conducted an exhaustive search for the most plausible druggable riboswitch using the RiboScan tool, subsequently subjecting its sequence to rigorous docking studies with ten distinct resveratrol derivatives through the PatchDock algorithm. In addition, we harnessed the power of ASO by designing and hybridizing five ASO sequences to silence the identified riboswitch target effectively. This comprehensive analysis pinpointed the glmS riboswitch as the most promising candidate for targeted intervention. Molecular docking results uncovered the exceptional inhibitory potential of resveratrol derivatives, with particular emphasis on ZINC۰۰۰۱۰۰۸۲۷۹۶۰, which emerged as a lead natural inhibitor. Furthermore, the ASO sequences, meticulously designed for their intended purpose, exhibited compelling efficacy in terms of hybrid free energy, RNA-RNA docking interactions, and a remarkably low probability of causing off-target effects within the human transcriptome. Taken together, our findings underscore the significant promise of both resveratrol derivatives and the ASO candidates as potent inhibitors of the glmS riboswitch in MRSA. These results warrant not only further consideration, but also rigorous experimental validation to pave the way for innovative strategies in combating the menace posed by MRSA.

Keywords:

Staphylococcus aureus , Methicillin resistant , riboswitch , Antisense oligonucleotides , Resveratrol , Molecular docking