טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentFridman Micha
SubjectNew Approaches towards the Development of Neomycin B Based
Aminoglycoside Antibiotics
DepartmentDepartment of Chemistry
Supervisor Professor Timor Baasov


Abstract


The rapid spread of antibiotic resistance in pathogenic bacteria has prompted a continuing search for new potential antibiotics. In our research we aimed to employ strategy, especially chemical modification of clinically used drugs, to circumvent existing bacterial resistance mechanisms and thereby to restore usefulness to antibacterials that have become compromised by resistance.

We chose the clinically used aminoglycoside antibiotic neomycin B as our lead compound for modifications. The addition of an extra sugar ring(s) at C- 5” of neomycin B, afforded a series of pseudo-oligosaccharides. These structures keep the whole antibiotic constitution intact while the extended sugar ring of each structure was designed in a manner that incorporates potential functionalities directed to improve its recognition to the target ribosomal RNA. Some of the new structures exhibited a significant improvement of the antibacterial activity against both pathogenic and resistant strains.

                In the second part of this research we aimed to utilize our new compounds for the treatment of anthrax. Anthrax is an infectious disease caused by the bacterium Bacillus anthracis. The anthrax lethal factor (LF), a Zn-dependent endopeptidase, has a major role in the development and virulence of anthrax. As neomycin B was found to be one of the most potent inhibitor of LF, we designed a series of neomycin B-based structures to improve the inhibition potency against the anthrax LF.

All of the compounds were found to be competitive inhibitors of LF with the inhibition potencies ranging from 2-53 times better than neomycin B.  Furthermore, some of the new compounds were found to possess significant antibacterial activity against B. anthracis, comparable to that of neomycin B.