A subsystems-based approach to the identification of drug targets in bacterial pathogens.
This chapter describes a three-stage approach to target identification based upon subsystem analysis. Subsystems analysis focuses on related metabolic pathways as a unit and is a biochemically-informed approach to target selection. The process involves three stages of analysis; the first stage, selection of the target subsystem, is guided by information about its essentiality and on the predicted vulnerability of the targeted pathway or enzyme to inhibition. The second stage involves analysis of the target subsystem by means of comparative genomics, including genome context analysis and metabolic reconstruction. The third stage evaluates the selection of the specific target genes within the subsystem by target prioritization and validation. The whole process allows for a careful consideration of spectrum, drugability, biological rationale and the metabolic role of the specific target within the context of an integrated circuit within a specific metabolic pathway.
Osterman
Andrei L
AL
Burnham Institute for Medical Research, Infectious and Inflammatory Disease Center, La Jolla, California, USA. osterman@burnham.org
Begley
Tadhg P
TP
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000235:genetics; D016680:Genome, Bacterial; D006801:Humans; D009243:NAD / Q000096:biosynthesis; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics
D000900:Anti-Bacterial Agents; D009243:NAD; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D009612:Nicotinamide-Nucleotide Adenylyltransferase; C038480:nicotinic acid mononucleotide adenylyltransferase