文档介绍：Integrated bacterial genomics for the discovery of novel antimicrobials
Taejin Ahn
Bric 2000/03/28
Introduction
23 bacterial species are sequenced
40 more sequencing projects in progress
Impact of
bacterial genomics
bioinformatics
second generation genomic technologies
on target identfication
assay development
lead pound characterization
Penicillin
Sulphonamides
No new chemical class have been introduced into the clinic for over 30 years
There are high expectations for microbial genomics in accelerating
Target discovery
Assay development
Genomics and target discovery
Whole genome sequence of 22 more bacterial species have been published
focus on antibacterial target for bacterial growth (bacterial virulence, resistance agains antibacterial agents)
Large-scale parative genomics
Genes of unknown function
Large-scale ics
Traditionaly
Random mutagenesis
Limit
1/3 of proteins are difficult to mutate
flase positive (involved in viablity in high temp)
Recently
transposon mutagenesis
Comparative genomics
parison of bacterial genomes a powerful tool for categorizing genes and their respective proteins
ex)
broad spectrum target
narrow spectrum target
Closely anism
ex)
Chlamydia trachomatis and Chlamydia paring by hybridization (DNA-array)
Mycobacterium tuberculosis and Mycobacterium bovis
parison to pathway
Genes of unknown function
Significant fraction of the genes have unknown functions ( 38%)
ex)
26 Function Unknown genes broadly conserved among diverse bacterial species
6 novel genes essential for the growth of and were identified
these genes were not included minimal gene set
Genomics and assay development
Traditionally
testing large libraries of natural products
low sensitivity
targets of the pounds are unknown
-> applying genomic technologies to investigate mode of action
In an alternative approach
finding inhibitor of individual proteins
ration of cell wall
function of target protein should be known
The latest
whole genomic ana