|M.Sc Student||Khononov Alina|
|Subject||Towards Catalytic Antibiotics|
|Department||Department of Chemistry||Supervisor||Professor Timor Baasov|
|Full Thesis text|
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 ColE3 along with the high resolution structures of aminoglycosides bound to their ribosomal binding site, we were able to rationally design such catalytic 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.
This thesis work is a part of team work that designed synthesized and evaluated new derivatives of neomycin B as potential new catalysts. In the frame of this program, I have synthesized a series of NeoB analogs modified at 4’ position. Initially, these compounds were tested against numerous bacteria and found that while all these compounds exhibited similar or lower antibacterial activity on the wild-type bacteria, against resistant strains they showed substantially better antibacterial activity than NeoB. However, all our attempts to show their catalytic function by following the cleavage of ribosomal RNA in ribosomal particles or in the model of ribosomal A-site, were unsuccessful. Based on the observed data, the team is currently searching for the design and synthesis of new generation derivatives with the desired catalytic function.