טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentChen Lilach
SubjectStructure-Toxicity Relationship Study of Aminoglycosides:
Towards New Generation of Antibiotics
DepartmentDepartment of Chemistry
Supervisor Professor Timor Baasov
Full Thesis textFull thesis text - English Version


Abstract

Aminoglycoside antibiotics have been used in the clinic for almost six decades. Aminoglycosides exert their therapeutic effect by inhibition of protein synthesis via interaction with the A site rRNA on the 16S domain of the bacterial ribosome. Because of their intensive clinical use, bacterial resistance to these drugs has become a serious public health problem. In addition, their high human toxicity largely limits the application against certain diseases. The origin of this toxicity is still controversial and probably results from a combination of different factors/mechanisms. Although several semisynthetic aminoglycosides have been introduced to clinical use during the last decades, the issue of their toxicity is still one of the major unresolved problems.

The goal of this research is to develop new generation of aminoglycosides with potent antibacterial activity and reduced toxicity.

From the available acute toxicity data it turns out that one of the factors that significantly increase the toxicity of aminoglycosides is the deoxygenation of hydroxyl group(s). The observed increase in the toxicity could be explained by an increase in the basicity of the adjacent amino group due to the removal of the neighboring electron-withdrawing oxygen atom. To test this issue we initially designed a new pseudo-disaccharide, compound 1, which consist a 3',4'-methylidene protection; the preservation of 3',4'-oxygens in 1 should keep the lower basicity of the 2'-NH2 group and subsequently lower its toxicity comparing to its 3',4'-dideoxy analog, Gentamine C1A. In addition, the methylidene group should protect 1 from various resistance enzymes. To test this hypothesis we determined pKa values of individual amino groups in 1, gentamine C1A and their 3',4'-dihydroxy analog along with their acute toxicity in mice. We found that the basicity of the 2'-amine is well correlated to acute toxicity data in mice: the increase in the basicity is associated with the toxicity increase, with the compound 1 being the least toxic.

Compound 1 was then used as a scaffold to generate a series of seventeen new structures. We were able to identify the lead structure exhibiting potent antibacterial activity and significantly low toxicity. From the observed data it was concluded that the 3',4'-methylidene protection can serve as useful tool for the generation of new aminoglycosides derivatives with potent antibacterial activity and low toxicity.