TOWARDS CATALYTIC ANTIBIOTICS

Boris Smolkin, Chemistry, Technion, Haifa, Israel
Michal Shavit, Chemistry, Technion, Haifa, Israel
Alina Vilensky, Chemistry, Technion, Haifa, Israel
Eli Shulman, Chemistry, Technion, Haifa, Israel
Moran Shalev, Chemistry, Technion, Haifa, Israel
Timor Baasov, Chemistry, Technion, Haifa, Israel

The key function and abundance of the bacterial ribosome make it an obvious target for antibacterial agents; and indeed, a large number of clinically used antibiotics exert their antibacterial activity by targeting this ribonucleoprotein machinery. 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 such catalytic agents with a potential to specifically cleave a highly conserved region within the ribosomal decoding site; therefore, resulting in a fast inactivation of translation machinery. The design principles along with the synthesis and preliminary activity tests of the target structures will be discussed.