Ribocil

Ribocil is chemical compound which is found to be a potent inhibitor of the FMN riboswitch, meaning it could serve as a promising lead compound for developing a new antibiotic class. The compound was discovered by Merck & Co. through a phenotypic screen of the Gram-positive bacteria Staphylococcus aureus. The binding mode of this small molecule to its binding site has been confirmed through the use of X-Ray crystallography.

Binding mode

The structure of ribocil versus previously discovered binders to the FMN riboswitch makes it unique, as it is not a structural analogue to the natural ligand, flavin mononucleotide. The binding mode of this compound has some similarities with ribocil, where the same π-π stacking interaction and two hydrogen bond is also conserved. Ribocil also makes two new contacts with the binding site which notably differs from FMN: a π-π interaction between the aminopyrimidine of ribocil and residue G62 and an edge-face π-interaction.

Challenges and derivatives

One major obstacle of using ribocil as a bona fide antibiotic is that although it kills bacteria in culture, Gram-positive organisms can scavenge riboflavin from their environment. While ribocil in itself has no activity towards Gram-negative bacteria, derivatives of ribocil which enhance the accumulative properties of these compounds have been synthesized to show whole-cell activity against wild-type strains of these bacteria.