Design And Synthesis Of Antibacterial Drug Based On The Structure Of Peptide Deformylase

In bacteria, protein synthesis initiates with a formylated methionyl tRNAt,Met so that the newly synthesized proteins are formylated at the amino terminus. PDF (peptide deformylase) is required to remove the formyl group from a newly synthesized polypeptide chain. This activity is essential for subsequent N-terminal processing by methionine aminopeptidase(Map). The enzyme is broadly conserved in more than 90 sequenced bacterial genomes and gene knock-out experiments showed that it is essential for the growth of E. coli, S. pneummoniae and S. aureus. It is interesting that the formylation is not necessary for the protein synthesis in mammals. The enzyme seems to be nonessential in mammals and may become an effective target for screening new antibacterial drugs.The biochemistry pathway of PDF for inhibiting bacteria is very clear now. Crystal structure of many kinds of PDF and the bioactive domain were established. Only 28 PDFs crystal structures were reported in 2002 when we started our project, but the number had went up to 47 in the beginning of 2006. The chemical structural types of reported inhibitors for PDF covered Hydroxamic acid derivatives, N-Hydroxycarbamide, Sulfhydryl peplides, Quizolinone, and the others, in which the first two types were mostly studied. BB-83698 from British Biotech & GeneSoft and VRC-4887 from Vicuron have been under clinic trial and showed attractive effects for Staphylococcus aureus, Enterococcus and some resistant pathogens. These inspiring achievements result in an active field that discover potential antibacterial agents from investigation for PDF inhibitors.