Design and Synthesis of Bacterial Transglycosylase Inhibitors
Date Issued
2011
Date
2011
Author(s)
Chang, Jung-Hua
Abstract
The discovery of penicillin antibiotics has a great impact on the treatment of infections caused by bacteria. However, the emergence of drug resistance has become a serious threat to human health. There is an urgent need to develop new agents that are active against resistant bacteria. The major constituent of bacterial cell wall is the peptidoglycan, which allows bacteria to live in a variable internal osmotic environment. Transglycosylase (TGase) is located on the extracellular surface of the bacterial cell membrane, where it catalyzes the polymerization of lipid II to establish the bacterial cell wall. Thus, TGase can be a potential target for development of new antibiotics.
We designed and synthesized some potential transglycosylase inhibitors using 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), N-acetylglucosamine (GlcNAc) or benzene ring bearing several hydrogen-bonding groups to mimic the saccharide part of lipid II, the natural substrate of TGase. On the other hand, long chain malonate or phosphoglycerate, a characteristic motif of moenomycin, were used to mimic the long chain pyrophosphate part. We also elongated different lengths of terminal amine from phosphoglycerate in order to determine the effect of the distance from phosphoglycerate to the saccharide part of lipid II. These kinds of inhibitors are expected to block the process of transglycosylation by mimicking the transition state in lipid II polymerization.
Some potential transglycosylase (TGase) inhibitors were synthesized and subjected to HPLC-based TGase fluorescence assay and MIC assay. The results have revealed that compound 59 is the best inhibitor having complete inhibition of TGase at 100 μM, among the designed compounds based on the transition-state of lipid II polymerization. Compound 60 has 80% inhibition at 100 μM.
OOHOOPOOOHH2N59Bestinhibition(100%inhibitionat100uM)OOEtOOPOOOH6080%inhibitionat100uMH2N
Most derivatives of phosphoglycerate bearing a terminal amino group showed some inhibition against TGase at 100 μM according to the HPLC-based fluorescence assay; however, the inhibitory activity diminished after connection with DANA, GlcNAc or benzene ring bearing several hydrogen-bonding groups. Though the part of long chain pyrophosphate could be replaced by the phosphoglycerate, a characteristic motif of moenomycin in TGase binding, it cannot be replaced by malonates. Phosphoglycerate coupled with the terminal amine might play an important role in TGase inhibition. Modification of these active compounds may eventually lead to more efficient inhibitors of TGase.
Subjects
Transglycosylase
Inhibitors
SDGs
Type
thesis
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