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Proteomic Characterization and Target Identification Against Streptococcus mutans Under Bacitracin Stress Conditions Using LC-MS and Subtractive Proteomics.

ABSTRACT: The aim of the present study, is to identify potential targets against the highly pathogenic bacteria Streptococcus mutans that causes dental caries as well as the deadly infection of endocarditis. The powerful and highly sensitive technique of liquid chromatography-mass spectrometry (LC-MS/MS) identified 321 proteins of S. mutans when grown under stressful conditions induced by the antibiotic bacitracin. These 321 proteins were subjected to the insilico method of subtractive proteomics to screen out potential targets by utilizing different analyses like CD-HIT, non-homologous sequence screening, KEGG pathway, essentiality screening, gut-flora non-homology, and codon usage analysis. A database of essential proteins was employed to find sequence homology of non-paralogous proteins to determine proteins which are essential for bacterial survival. Cellular localization analysis of the selected proteins was done to localize them inside the cell along with physico-chemical characterization and druggability analysis. Using computational tools, 22 proteins out of 321, that are functionally distinguishable from their human counterparts and passed the criterion of a potential therapeutic candidate were identified. The selected proteins comprise central energy metabolic proteins, virulence factors, proteins of the sortase family, and essentiality factors. The presented analyses identified proteins of the sortase family, which appear as key therapeutic targets against caries infection. These proteins regulate a number of virulence factors, thus can be simultaneously inhibited to obstruct multiple virulence pathways.

SUBMITTER: Zaidi S

PROVIDER: S-EPMC8733428 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Highly specialized cells are fundamental for proper functioning of complex organs. Variations in cell-type specific gene expression and protein composition have been linked to a variety of diseases. Although single cell technologies have emerged as valuable tools to address this cellular heterogeneity, a majority of these workflows lack sufficient in situ resolution for functional classification of cells and are associated with extremely long analysis time, especially when it comes to in situ proteomics. In addition, lack of understanding of single cell dynamics within their native environment limits our ability to explore the altered physiology in disease development. This limitation is particularly relevant in the mammalian brain, where different cell types perform unique functions and exhibit varying sensitivities to insults. The hippocampus, a brain region crucial for learning and memory, is of particular interest due to its obvious involvement in various neurological disorders. Here, we present a combination of experimental and data integration approaches for investigation of cellular heterogeneity and functional disposition within the mouse brain hippocampus using MALDI Imaging mass spectrometry (MALDI-IMS) and shotgun proteomics (LC-MS/MS) coupled with laser-capture microdissection (LCM) along with spatial transcriptomics. Within the dentate gyrus granule cells we identified two proteomically distinct cellular subpopulations that are characterized by a substantial number of discriminative proteins. These cellular clusters contribute to the overall functionality of the dentate gyrus by regulating redox homeostasis, mitochondrial organization, RNA processing, and microtubule organization. Importantly, most of the identified proteins matched their transcripts, verifying the in situ protein identification and supporting their functional analyses. By combining high-throughput spatial proteomics with transcriptomics, our approach enables reliable near-single-cell scale identification of proteins and profiling of inter-cellular heterogeneity within similar cell-types in tissues. This methodology has the potential to be applied to different biological conditions and tissues, providing a deeper understanding of cellular subpopulations in situ.

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Proteomic Characterization and Target Identification Against Streptococcus mutans Under Bacitracin Stress Conditions Using LC-MS and Subtractive Proteomics.

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