Towards Catalytic Antibiotics

Aminoglycosides are broad-spectrum antibiotics that selectively target the bacterial ribosome leading to a series of miscoding and translation inhibition events, finally resulting in bacterial death. Unfortunately, the prolonged clinical use of aminoglycosides has resulted in rapid evolvement of resistant bacterial strains that severely restrict their use. Over the last few decades many synthetic analogs of natural aminoglycosides have been synthesized. These analogs demonstrated similar activity to their parent scaffold or a rather poor antibacterial activity. Moreover, when these derivatives were introduced to clinical use, the appearance of resistant bacteria was rather fast. This dire public health concern has revived an interest in the discovery and development of novel strategies that can address the problem of growing antibacterial resistance.

One such potential strategy is the development of catalytic antibiotics that will be able to induce a fast and irreversible inactivation of their target. The possible benefits include: activity at lower dosages and subsequent elimination of side effects, activity against drug-resistant bacteria, and reduced potential for generating new resistance. Using high resolution structures of aminoglycosides bound to their ribosomal binding site, we were able to rationally design a series of structures with a potential to specifically bind and catalytically cleave a highly conserved region within the ribosomal decoding site RNA; therefore, resulting in a fast inactivation of translation machinery. These compounds contain a 2-ring aminoglycoside scaffold or the whole aminoglycoside structure and are substituted with di-amine or macrocyclic metal complexes as “catalytic warheads”. Metal complexes along with the general acid/general base catalytic groups are part of artificial nucleases and play crucial role in hydrolysis of phosphodiester bond. The design principles along with the synthesis and preliminary biological evaluation of the target structures will be discussed.