Streptococcus pneumoniae as a genomics platform for broad-spectrum antibiotic discovery

Glass, John I.; Belanger, Aimee E.; Robertson, Gregory T.

doi:10.1016/s0959-4388(02)90328-4

Cited by 15 publications

(10 citation statements)

References 31 publications

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“…The post-genomic era The availability of genomic sequence data for numerous Gram-positive bacteria, including three pneumococcal strains, has facilitated the identification of additional pneumococcal surface molecules (e.g., [15,27,28]). These analyses have led to the identification of many new surface molecules compared to the pregenomic era, and have often relied on searches for specific signatures in sequences of open reading frames (ORF) coding for such proteins.…”

Section: Introductionmentioning

confidence: 99%

Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Jedrzejas¹

2007

Cell. Mol. Life Sci.

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Bacteria present a variety of molecules either on their surface or in a cell-free form. These molecules take part in numerous processes in the interactions with their host, with its tissues and other molecules. These molecules are essential to bacterial pathogenesis either during colonization or the spread/invasion stages, and most are virulence factors. This review is focused on such molecules using Streptococcus pneumoniae, a Gram-positive bacterium, as an example. Selected surface proteins are introduced, their structure described, and, whenever available, their mechanisms of function on an atomic level are explained. Such mechanisms for hyaluronate lyase, pneumococcal surface protein A, pneumolysin, histidine-triad and fibronectin-binding proteins are discussed. Elucidation of molecular mechanisms of virulence factors is essential for the understanding of bacteria and their functional properties. Structural biology appears pivotal for these studies, as structural and mechanistic insights facilitate rational approach to the development of new treatments.

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Section: Introductionmentioning

confidence: 99%

Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Jedrzejas¹

2007

Cell. Mol. Life Sci.

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“…The high morbidity and mortality associated with pneumococcal diseases are exacerbated by the rate at which this organism is acquiring resistance to multiple antibiotics and the limitation in the clinical efficacy of current vaccines, especially for high-risk groups, such as young children and the elderly (5,20). A more detailed understanding of S. pneumoniae virulence is likely to provide new vaccine candidates and targets for antibacterial drugs (12,16,38).…”

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confidence: 99%

Role of HtrA in the Virulence and Competence of Streptococcus pneumoniae

et al. 2004

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HtrA is a major virulence factor of Streptococcus pneumoniae (the pneumococcus). Deletion of the gene for HtrA from strain D39 of the pneumococcus completely abolished its virulence in mouse models of pneumonia and bacteremia, while the virulence of a second strain (TIGR4) was dramatically reduced. HtrA-negative mutants induced much less inflammation in the lungs during pneumonia than the wild type. HtrA is involved in the ability of the pneumococcus to grow at high temperatures, to resist oxidative stress, and to undergo genetic transformation. The expression and cellular location of several known virulence factors of the pneumococcus were not affected by the lack of HtrA.

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“…S. pneumoniae is a major pathogen suitable as a model system for biomedical studies [28]. In order to select cHPs of S. pneumoniae R6 that were truly uncharacterised and that were chemically amenable to experimental analysis, 858 potential cHPs were initially selected (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Inspecting the potential physiological and biomedical value of 44 conserved uncharacterised proteins of Streptococcus pneumoniae

et al. 2014

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BackgroundThe major Gram-positive coccoid pathogens cause similar invasive diseases and show high rates of antimicrobial resistance. Uncharacterised proteins shared by these organisms may be involved in virulence or be targets for antimicrobial therapy.ResultsForty four uncharacterised proteins from Streptococcus pneumoniae with homologues in Enterococcus faecalis and/or Staphylococcus aureus were selected for analysis. These proteins showed differences in terms of sequence conservation and number of interacting partners. Twenty eight of these proteins were monodomain proteins and 16 were modular, involving domain combinations and, in many cases, predicted unstructured regions. The genes coding for four of these 44 proteins were essential. Genomic and structural studies showed one of the four essential genes to code for a promising antibacterial target. The strongest impact of gene removal was on monodomain proteins showing high sequence conservation and/or interactions with many other proteins. Eleven out of 40 knockouts (one for each gene) showed growth delay and 10 knockouts presented a chaining phenotype. Five of these chaining mutants showed a lack of putative DNA-binding proteins. This suggest this phenotype results from a loss of overall transcription regulation. Five knockouts showed defective autolysis in response to penicillin and vancomycin, and attenuated virulence in an animal model of sepsis.ConclusionsUncharacterised proteins make up a reservoir of polypeptides of different physiological importance and biomedical potential. A promising antibacterial target was identified. Five of the 44 examined proteins seemed to be virulence factors.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-652) contains supplementary material, which is available to authorized users.

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Streptococcus pneumoniae as a genomics platform for broad-spectrum antibiotic discovery

Cited by 15 publications

References 31 publications

Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Unveiling molecular mechanisms of bacterial surface proteins: Streptococcus pneumoniae as a model organism for structural studies

Role of HtrA in the Virulence and Competence of Streptococcus pneumoniae

Inspecting the potential physiological and biomedical value of 44 conserved uncharacterised proteins of Streptococcus pneumoniae

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