טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentSmolkin Boris
SubjectTowards Catalytic Antibiotics
DepartmentDepartment of Chemistry
Supervisor Professor Timor Baasov
Full Thesis textFull thesis text - English Version


Abstract

Aminoglycosides are highly potent, broad-spectrum antibiotics that exert their bactericidal therapeutic effect by selectively binding to the aminoacyl-tRNA binding site (A-site) of the bacterial 16S rRNA, thereby interfering with translational fidelity during protein synthesis. The appearance of bacterial strains resistant to these drugs, as well as their relative toxicity, have encouraged an extensive search towards the goal of obtaining novel molecular designs with improved antibacterial activity and reduced toxicity. However, unfortunately, it has been well documented that once a new antibiotic is introduced into the clinic, whether it is a novel chemical entity acting at distinct bacterial target or a semisynthetic derivative that counters the resistance to its parent drug, it is only a short matter of time until new resistance will yet again emerge and create a public health problem. Thus, the emerging and sustained resistance to currently available antibiotics, and the poor pipeline of new antibacterials, urgently calls for the development of new strategies that can address the problem of growing antibacterial resistance.

In this work, we would like to present one such potential strategy: the development of catalytic antibiotics that will be able to induce cleavage of a crucial chemical bond at their binding site via catalytic manner, resulting in a fast inactivation of their target site. This strategy is based on a chemical modification of existing antibiotic in order to make it a catalyst. The possible benefits include: i) lower dosages that leads to lower toxicity, ii) activity against resistant bacteria, and iii) reduced potential for generating new resistance. Based on the recently published structural and mechanistic data of the natural bacteriocin Colicin E3 along with the high resolution structures of aminoglycosides bound to their ribosomal binding site, we were able to rationally design such agents with high potential to specifically cleave a highly conserved region within the ribosomal decoding site; therefore, resulting in a fast inactivation of translation machinery.

The main motivation towards achieving this goal is that no such drugs exist and, this research can potentially pave a new avenue for antibiotics development.

In order to reach a successful lead compound, a series of Neamine/Neomycin B analogs modified at 4’ position were designed and synthesized. These compounds were tested for the desired activities, including, antibacterial activities towards both wild type and resistance bacteria, inhibition of translation and RNAse activity. Although the tested compounds exhibited similar antibacterial activity against wild type bacteria, against resistant strains they showed substantially better antibacterial activity than Neomycin B. Especially good activities were observed against Methicillin-resistant Staphylococcus aureus strains. Interestingly, three of the 4’-amide derivatives showed 2-times stronger inhibition of protein synthesis in comparison to Neomycin B and the other clinically used aminoglycosides.