Defining the core essential genome of Pseudomonas aeruginosa

Genomics offered the promise of transforming antibiotic discovery by revealing many new essential genes as good targets, but the results fell short of the promise. While numerous factors contributed to the disappointing yield, one factor was that essential genes for a bacterial species were often de...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-05, Vol.116 (20), p.10072-10080
Main Authors: Poulsen, Bradley E., Yang, Rui, Clatworthy, Anne E., White, Tiantian, Osmulski, Sarah J., Li, Li, Penaranda, Cristina, Lander, Eric S., Shoresh, Noam, Hung, Deborah T.
Format: Article
Language:English
Subjects:
Antibiotics
Biological Sciences
Convergence
DNA Transposable Elements
Drug discovery
Fitness
Gene sequencing
Genes
Genes, Essential
Genome, Bacterial
Genomes
Genomics
Growth conditions
Insertion
Mathematical models
Models, Statistical
PNAS Plus
Pseudomonas aeruginosa
Pseudomonas aeruginosa - genetics
Reproductive fitness
Statistical models
Strains (organisms)
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Summary:Genomics offered the promise of transforming antibiotic discovery by revealing many new essential genes as good targets, but the results fell short of the promise. While numerous factors contributed to the disappointing yield, one factor was that essential genes for a bacterial species were often defined based on a single or limited number of strains grown under a single or limited number of in vitro laboratory conditions. In fact, the essentiality of a gene can depend on both the genetic background and growth condition. We thus developed a strategy for more rigorously defining the core essential genome of a bacterial species by studying many pathogen strains and growth conditions. We assessed how many strains must be examined to converge on a set of core essential genes for a species. We used transposon insertion sequencing (Tn-Seq) to define essential genes in nine strains of Pseudomonas aeruginosa on five different media and developed a statistical model, FiTnEss, to classify genes as essential versus nonessential across all strain–medium combinations. We defined a set of 321 core essential genes, representing 6.6% of the genome. We determined that analysis of four strains was typically sufficient in P. aeruginosa to converge on a set of core essential genes likely to be essential across the species across a wide range of conditions relevant to in vivo infection, and thus to represent attractive targets for novel drug discovery.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1900570116