Using Phosphoglycerate Octyl Ether-Lipid Derivatives to Study the Inhibition of Bacterial Transglycosylases
Date Issued
2014
Date
2014
Author(s)
Tsai, Wan-Chen
Abstract
In this day and age, antibiotics are used to treat people for bacterial infections. However, abuse of antibiotics also leads to the appearance of multi-drug resistant bacteria. There is an urgent need to develop new agents that are active against multi-drug resistant bacteria. The main constituent of bacteria cell wall is peptidoglycan, which is responsible for a defined cell shape to allow bacteria to live in a variable internal osmotic environment. Transpeptidase (TPase) and transglycosylase (TGase) are two major enzymes which can catalyze the synthesis of bacteria cell wall. TGase is located on the external surface of bacterical cell membrane, so that it is unnecessary for inhibitors to enter cytoplasm. We consider TGase as a promising antibiotic target due to its essential function and ready accessibility.
We have designed and synthesized some potential transglycosylase inhibitors with an aryl moiety bearing several hydrogen-bonding groups to mimic the saccharide part of lipid II, the nature substrate of TGase. In addition, a long chain phosphoglycerate was used to mimic the long chain pyrophosphate part of lipid II. These inhibitors are designed to block the process of transglycosylation by mimicking the transition state in lipid II polymerization. Some potential transglycosylase inhibitors were synthesized and subjected to the HPLC-based TGase fluorescence assay and MIC assay. Among these derivatives of phosphoglycerate with the aryl moiety bearing hydrogen-bonding groups showed the best MIC value of 100 μM against Staphylococcus aureus. However, it showed no inhibition against TGase at same concentration. Among all of the transglycosylase inhibitors designed in our laboratory, we considered that it is necessary to retain phosphate structure and introduce benzene structure bearing hydrogen-bonding groups (e.g. OH). We hope that through the interaction between benzene ring and amide side chain and further hydrogen bonding might improve the inhibitory activity to act as efficient TGase inhibitors.
Subjects
轉醣酶抑制劑
Type
thesis
File(s)![Thumbnail Image]()
Loading...
Name
ntu-103-R01223149-1.pdf
Size
23.32 KB
Format
Adobe PDF
Checksum
(MD5):7adef45d3e9cba5bb5f20a333b0c1bff