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Essential Genes in the Core Genome of the Human Pathogen Streptococcus pyogenes.

Le Breton Y, Belew AT, Valdes KM, Islam E, Curry P, Tettelin H, Shirtliff ME, El-Sayed NM, McIver KS - Sci Rep (2015)

Bottom Line: A large proportion of GAS essential genes corresponded to key cellular processes and metabolic pathways, and 177 were found conserved within the GAS core genome established from 20 available GAS genomes.Selected essential genes were validated using conditional-expression mutants.Finally, comparison to previous essentiality analyses in S. sanguinis and S. pneumoniae revealed significant overlaps, providing valuable insights for the development of new antimicrobials to treat infections by GAS and other pathogenic streptococci.

View Article: PubMed Central - PubMed

Affiliation: 1] [2].

ABSTRACT
Streptococcus pyogenes (Group A Streptococcus, GAS) remains a major public health burden worldwide, infecting over 750 million people leading to over 500,000 deaths annually. GAS pathogenesis is complex, involving genetically distinct GAS strains and multiple infection sites. To overcome fastidious genetic manipulations and accelerate pathogenesis investigations in GAS, we developed a mariner-based system (Krmit) for en masse monitoring of complex mutant pools by transposon sequencing (Tn-seq). Highly saturated transposant libraries (Krmit insertions in ca. every 25 nucleotides) were generated in two distinct GAS clinical isolates, a serotype M1T1 invasive strain 5448 and a nephritogenic serotype M49 strain NZ131, and analyzed using a Bayesian statistical model to predict GAS essential genes, identifying sets of 227 and 241 of those genes in 5448 and NZ131, respectively. A large proportion of GAS essential genes corresponded to key cellular processes and metabolic pathways, and 177 were found conserved within the GAS core genome established from 20 available GAS genomes. Selected essential genes were validated using conditional-expression mutants. Finally, comparison to previous essentiality analyses in S. sanguinis and S. pneumoniae revealed significant overlaps, providing valuable insights for the development of new antimicrobials to treat infections by GAS and other pathogenic streptococci.

No MeSH data available.


Related in: MedlinePlus

GAS essential genes correlate to key metabolic pathways and cellular functions.Schematics of the pathways for (A) Glycolysis, (B) Peptidoglycan biosynthesis, and (C) Fatty acid biosynthesis are shown, including reactants/products (black font) and genes encoding key enzymes (blue font). Integrated Bayesian analysis results for key enzymes are shown for GAS 5448 (circles) and NZ131 (diamonds) with "essential" genes in red; "critical" genes in yellow; "non-essential" genes in green; and "non conclusive" genes in grey.
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f4: GAS essential genes correlate to key metabolic pathways and cellular functions.Schematics of the pathways for (A) Glycolysis, (B) Peptidoglycan biosynthesis, and (C) Fatty acid biosynthesis are shown, including reactants/products (black font) and genes encoding key enzymes (blue font). Integrated Bayesian analysis results for key enzymes are shown for GAS 5448 (circles) and NZ131 (diamonds) with "essential" genes in red; "critical" genes in yellow; "non-essential" genes in green; and "non conclusive" genes in grey.

Mentions: The integrated essentiality results from M1T1 5448 and M49 NZ131 were compared (Fig. 3 and Table S7). Of the genes found "Essential" in 5448 (227) and NZ131 (241), 187 were found to overlap in both strains and most likely represent essential genes shared by many GAS strains (Fig. 3A and Table S7). Comparison of the GAS 5448 and NZ131 datasets revealed the importance of conserved essential genes in key metabolic pathways such as glycolysis (Fig. 4A), peptidoglycan biosynthesis (Fig. 4B) and fatty acid synthesis (Fig. 4C).


Essential Genes in the Core Genome of the Human Pathogen Streptococcus pyogenes.

Le Breton Y, Belew AT, Valdes KM, Islam E, Curry P, Tettelin H, Shirtliff ME, El-Sayed NM, McIver KS - Sci Rep (2015)

GAS essential genes correlate to key metabolic pathways and cellular functions.Schematics of the pathways for (A) Glycolysis, (B) Peptidoglycan biosynthesis, and (C) Fatty acid biosynthesis are shown, including reactants/products (black font) and genes encoding key enzymes (blue font). Integrated Bayesian analysis results for key enzymes are shown for GAS 5448 (circles) and NZ131 (diamonds) with "essential" genes in red; "critical" genes in yellow; "non-essential" genes in green; and "non conclusive" genes in grey.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440532&req=5

f4: GAS essential genes correlate to key metabolic pathways and cellular functions.Schematics of the pathways for (A) Glycolysis, (B) Peptidoglycan biosynthesis, and (C) Fatty acid biosynthesis are shown, including reactants/products (black font) and genes encoding key enzymes (blue font). Integrated Bayesian analysis results for key enzymes are shown for GAS 5448 (circles) and NZ131 (diamonds) with "essential" genes in red; "critical" genes in yellow; "non-essential" genes in green; and "non conclusive" genes in grey.
Mentions: The integrated essentiality results from M1T1 5448 and M49 NZ131 were compared (Fig. 3 and Table S7). Of the genes found "Essential" in 5448 (227) and NZ131 (241), 187 were found to overlap in both strains and most likely represent essential genes shared by many GAS strains (Fig. 3A and Table S7). Comparison of the GAS 5448 and NZ131 datasets revealed the importance of conserved essential genes in key metabolic pathways such as glycolysis (Fig. 4A), peptidoglycan biosynthesis (Fig. 4B) and fatty acid synthesis (Fig. 4C).

Bottom Line: A large proportion of GAS essential genes corresponded to key cellular processes and metabolic pathways, and 177 were found conserved within the GAS core genome established from 20 available GAS genomes.Selected essential genes were validated using conditional-expression mutants.Finally, comparison to previous essentiality analyses in S. sanguinis and S. pneumoniae revealed significant overlaps, providing valuable insights for the development of new antimicrobials to treat infections by GAS and other pathogenic streptococci.

View Article: PubMed Central - PubMed

Affiliation: 1] [2].

ABSTRACT
Streptococcus pyogenes (Group A Streptococcus, GAS) remains a major public health burden worldwide, infecting over 750 million people leading to over 500,000 deaths annually. GAS pathogenesis is complex, involving genetically distinct GAS strains and multiple infection sites. To overcome fastidious genetic manipulations and accelerate pathogenesis investigations in GAS, we developed a mariner-based system (Krmit) for en masse monitoring of complex mutant pools by transposon sequencing (Tn-seq). Highly saturated transposant libraries (Krmit insertions in ca. every 25 nucleotides) were generated in two distinct GAS clinical isolates, a serotype M1T1 invasive strain 5448 and a nephritogenic serotype M49 strain NZ131, and analyzed using a Bayesian statistical model to predict GAS essential genes, identifying sets of 227 and 241 of those genes in 5448 and NZ131, respectively. A large proportion of GAS essential genes corresponded to key cellular processes and metabolic pathways, and 177 were found conserved within the GAS core genome established from 20 available GAS genomes. Selected essential genes were validated using conditional-expression mutants. Finally, comparison to previous essentiality analyses in S. sanguinis and S. pneumoniae revealed significant overlaps, providing valuable insights for the development of new antimicrobials to treat infections by GAS and other pathogenic streptococci.

No MeSH data available.


Related in: MedlinePlus