A bacterial enzyme with a highly unusual mechanism may lead to a range of novel antibiotics.
A bacterial enzyme with a highly unusual mechanism may lead to a range of novel antibiotics.
A team of Canadian, US and UK researchers, led by John Vederas of the University of Alberta, believed that forming specific inhibitors of enzymes called diaminopimelic acid (DAP) epimerase would lead to antimicrobial agents that have low toxicity to mammals. The team identified these as potential targets for the development of new antibiotics.
They formed, for the first time, optically active aziridino diaminopimelates (azi-DAP). These are small, but highly functionalised and chemically very sensitive inactivators of DAP epimerase.
To evaluate them as DAP epimerase inhibitors, difficult because of the instability of azi-DAP isomers, crystal structures of a substrate analogue like azi-DAP bound in the active site of the enzyme were analysed.
’Successful synthesis and inhibition of DAP epimerase has allowed crystal structures to be obtained that should lead to a better understanding of the mechanism,’ said Vederas. ’A future challenge may be to make a small molecule model that catalyses such a reaction. In addition design of stable inhibitors of enzymes in the DAP pathway should give new antibiotics that are non-toxic to mammals,’ he said.
Elinor L Richards
References
C M Diaper, A Sutherland, B Pillai, M N G James, P Semchuk, J S Blanchard and J C Vederas, Org. Biomol. Chem., 2005, 3, 4402 (DOI: 10.1039/<MAN>b513409a</MAN>)
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