טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentShavit-Kishkober Michal
SubjectNovel Strategies to Fight Bacterial Resistance
DepartmentDepartment of Chemistry
Supervisor Professor Timor Baasov
Full Thesis textFull thesis text - English Version


Abstract

The emerging resistance to currently available antibiotics, and the poor prospects for new antibacterial agents, prompt urgent call for the development of new strategies to battle the growing antibacterial resistance. Toward these ends, we investigated two different strategies. One strategy considers the unique potential of dual-action hybrid antibiotics: two antibiotics covalently linked. The possible benefits include: i) activity against drug-resistant bacteria, ii) an expanded spectrum of activity, and iii) reduced potential for generating bacterial resistance.

Our group recently reported the synthesis and evaluation of a series of neomycin B-ciprofloxacin hybrids. While these hybrids exhibited dual mode of action and substantial antibacterial activity, they exhibited antagonistic behavior in comparison to the mother drugs. A case study of one hybrid showed delay in resistance development in bacteria. To our knowledge, this provided the first demonstration of a hybrid delaying the emergence of resistance development in bacteria.

Our main goal was to design, synthesize and test additional hybrid structures in order to further establish the concept; namely, whether the antagonistic combination in a hybrid drug will delay the development of resistance as a general phenomenon, or if it was a distinct observation with the particular hybrid. 

Towards these ends, we have designed and synthesized a library of kanamycin A-ciprofloxacin hybrids, connected via 1,2,3-triazole linkers. Their antibiotic activity was tested against a wide range of bacterial strains, including resistant strains. We demonstrated that while the hybrids exhibit significant antibacterial activity, they also have antagonistic behavior. Two case studies of these hybrids demonstrated significant delay in the development of resistance in bacteria. This provides support to the general concept that antagonistic hybrids of flouro-quinolones and aminoglycosides inhibit resistance development in bacteria.

The second strategy, which is rather new and has been initiated here for the first time, is the development of a catalytic antibiotic. This approach is based on a chemical modification of existing antibiotic in order to make it a catalyst. The possible benefits include: i) lower dosages and consequencing lower toxicity, ii) activity against resistant bacteria, and iii) reduced potential for generating new resistance. The main motivation towards achieving this goal was/is that no such drugs exist and, this research can potentially pave a new avenue for antibiotics development.

Our group rationally designed and synthesized a series of NeoB analogs modified at 4’ position. Initially I tested these compounds 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. Interestingly, three of the 4’-amide derivatives showed 2-times stronger inhibition of protein synthesis in comparison to NeoB and the other clinically used aminoglycosides. 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.