RnpA inhibitors as potential antistaphylococcal agents: computational design, synthesis, and biological evaluation

Staphylococcus aureus is one of the most important strains, from a clinical point of view. Indeed, in specific conditions, such as weakness of the immune system of the host, this bacterium can lead to severe pathologies. Therefore, antistaphylococcal agents able to acts on resistant germs are an urgent unmet medical need. The S. aureus protein RnpA has been recently recognized as a potential target for the development of antimicrobials, since it is involved in two crucial processes of the bacterium: mRNA degradation and tRNA maturation. In the present work, for the first time in literature a computational model is reported. A Hotspots Maps calculation has been performed, to define one main area as the potential binding site. Then, RNPA2000 and JC1/2, known RnpA inhibitors, were docked allowing us to identify the key interactions between these inhibitors and RnpA. After this validation, an in-depth SAR analysis of RnpA inhibitors was achieved, designing and computationally evaluating a series of novel derivatives. For the obtainment of this novel set of compounds, peculiar synthetic pathways were designed and refined. After their purification and characterization, all the compounds underwent both in vitro and cellular assays, to evaluate their capability to interact and to inhibit RnpA, as well as their antimicrobial activity. Several compounds showed promising activity, in terms of MIC and inhibitory activity vs RnpA. This work opens up for further computational-guided drug design of RnpA inhibitors, aiming at obtaining potent inhibitors.