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Gradients in gene essentiality reshape antibacterial research.

ABSTRACT: Essential genes encode the processes that are necessary for life. Until recently, commonly applied binary classifications left no space between essential and non-essential genes. In this review, we frame bacterial gene essentiality in the context of genetic networks. We explore how the quantitative properties of gene essentiality are influenced by the nature of the encoded process, environmental conditions and genetic background, including a strain's distinct evolutionary history. The covered topics have important consequences for antibacterials, which inhibit essential processes. We argue that the quantitative properties of essentiality can thus be used to prioritize antibacterial cellular targets and desired spectrum of activity in specific infection settings. We summarize our points with a case study on the core essential genome of the cystic fibrosis pathobiome and highlight avenues for targeted antibacterial development.

SUBMITTER: Hogan AM

PROVIDER: S-EPMC9075587 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Gradients in gene essentiality reshape antibacterial research.

Hogan Andrew M AM Cardona Silvia T ST

FEMS microbiology reviews 20220501 3

Essential genes encode the processes that are necessary for life. Until recently, commonly applied binary classifications left no space between essential and non-essential genes. In this review, we frame bacterial gene essentiality in the context of genetic networks. We explore how the quantitative properties of gene essentiality are influenced by the nature of the encoded process, environmental conditions and genetic background, including a strain's distinct evolutionary history. The covered to ...[more]

PMID: 35104846

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Project description:BACKGROUND:Essentiality assays are important tools commonly utilized for the discovery of gene functions. Growth/no growth screens of single gene knockout strain collections are also often utilized to test the predictive power of genome-scale models. False positive predictions occur when computational analysis predicts a gene to be non-essential, however experimental screens deem the gene to be essential. One explanation for this inconsistency is that the model contains the wrong information, possibly an incorrectly annotated alternative pathway or isozyme reaction. Inconsistencies could also be attributed to experimental limitations, such as growth tests with arbitrary time cut-offs. The focus of this study was to resolve such inconsistencies to better understand isozyme activities and gene essentiality. RESULTS:In this study, we explored the definition of conditional essentiality from a phenotypic and genomic perspective. Gene-deletion strains associated with false positive predictions of gene essentiality on defined minimal medium for Escherichia coli were targeted for extended growth tests followed by population sequencing and transcriptome analysis. Of the twenty false positive strains available and confirmed from the Keio single gene knock-out collection, 11 strains were shown to grow with longer incubation periods making these actual true positives. These strains grew reproducibly with a diverse range of growth phenotypes. The lag phase observed for these strains ranged from less than one day to more than 7 days. It was found that 9 out of 11 of the false positive strains that grew acquired mutations in at least one replicate experiment and the types of mutations ranged from SNPs and small indels associated with regulatory or metabolic elements to large regions of genome duplication. Comparison of the detected adaptive mutations, modeling predictions of alternate pathways and isozymes, and transcriptome analysis of KO strains suggested agreement for the observed growth phenotype for 6 out of the 9 cases where mutations were observed. CONCLUSIONS:Longer-term growth experiments followed by whole genome sequencing and transcriptome analysis can provide a better understanding of conditional gene essentiality and mechanisms of adaptation to such perturbations. Compensatory mutations are largely reproducible mechanisms and are in agreement with genome-scale modeling predictions to loss of function gene deletion events.

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Gradients in gene essentiality reshape antibacterial research.

Publications

Gradients in gene essentiality reshape antibacterial research.

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