title: Regulation of both gene expression and protein stability provides genetically assisted target evaluation (GATE) for microbial target validation.
abstract: The attempt to develop novel antibiotics, active against organisms resistant to current therapies, has led researchers to seek and explore new drug targets. The rapid sequencing and analysis of entire microbial genomes has identified large numbers of genes that may be sufficiently different from their human counterparts to be exploited as targets for antimicrobial treatment. As a first step, the importance of the various putative targets for microbial growth and survival must be assessed. Emerging validation technologies are becoming increasingly sophisticated and, in certain cases, allow prioritisation of the best targets. In this paper, genetically assisted target evaluation (GATE) is introduced as a versatile target validation technology. GATE concomitantly manipulates both synthesis and stability of the targeted protein using copper ions as an effector. This technology allows rapid quantitation of the lethal consequences of inactivation of targeted gene products in Saccharomyces cerevisiae. Additional tools can then be applied to extend these results into pathogenic organisms, such as Candida albicans.
authors.affiliation: Anadys Pharmaceuticals, Inc., 9050 Camino Santa Fe, San Diego, CA 92121, USA.
authors.forename: E T
authors.initials: ET
authors.lastname: Buurman
authors.forename: J D
authors.initials: JD
authors.lastname: Bradley
authors.forename: C E
authors.initials: CE
authors.lastname: Donnelly
authors.forename: J B
authors.initials: JB
authors.lastname: Moore
authors.forename: J M
authors.initials: JM
authors.lastname: Healy
authors.forename: D R
authors.initials: DR
authors.lastname: Averett
authors.forename: C M
authors.initials: CM
authors.lastname: Thompson
authors.forename: C R
authors.initials: CR
authors.lastname: Wobbe
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*
chemical_list: D000890:Anti-Infective Agents; D011506:Proteins