Cell
Volume 144, Issue 1, 7 January 2011, Pages 143-156
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Phenotypic Landscape of a Bacterial Cell

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Summary

The explosion of sequence information in bacteria makes developing high-throughput, cost-effective approaches to matching genes with phenotypes imperative. Using E. coli as proof of principle, we show that combining large-scale chemical genomics with quantitative fitness measurements provides a high-quality data set rich in discovery. Probing growth profiles of a mutant library in hundreds of conditions in parallel yielded > 10,000 phenotypes that allowed us to study gene essentiality, discover leads for gene function and drug action, and understand higher-order organization of the bacterial chromosome. We highlight new information derived from the study, including insights into a gene involved in multiple antibiotic resistance and the synergy between a broadly used combinatory antibiotic therapy, trimethoprim and sulfonamides. This data set, publicly available at http://ecoliwiki.net/tools/chemgen/, is a valuable resource for both the microbiological and bioinformatic communities, as it provides high-confidence associations between hundreds of annotated and uncharacterized genes as well as inferences about the mode of action of several poorly understood drugs.

Highlights

► Phenomic profiling of E. coli identifies thousands of mutant growth phenotypes ► Patterns of growth phenotypes reveal new functional connections between genes ► Uncharacterized genes linked to many phenotypes tend to be evolutionarily restricted ► Mutant phenotypes generate insights into drug mode of action and drug synergy

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Present address: UCLA School of Dentistry, 10833 Le Conte Avenue, Los Angeles, CA 90095-1762, USA

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Present address: Massachusetts General Hospital, 50 Staniford Street, Boston, MA 02114, USA