Dataset Information

Pathogen-associated gene discovery workflows for novel antivirulence therapeutic development.

ABSTRACT: Novel therapeutics to manage bacterial infections are urgently needed as the impact and prevalence of antimicrobial resistance (AMR) grows. Antivirulence therapeutics are an alternative approach to antibiotics that aim to attenuate virulence rather than target bacterial essential functions, while minimizing microbiota perturbation and the risk of AMR development. Beyond known virulence factors, pathogen-associated genes (PAGs; genes found only in pathogens to date) may play an important role in virulence or host association. Many identified PAGs encode uncharacterized hypothetical proteins and represent an untapped wealth of novel drug targets. Here, we review current advances in antivirulence drug research and development, including PAG identification, and provide a comprehensive workflow from the discovery of antivirulence drug targets to drug discovery. We highlight the importance of integrating bioinformatic/genomic-based methods for novel virulence factor discovery, coupled with experimental characterization, into existing drug screening platforms to develop novel and effective antivirulence drugs.

SUBMITTER: Lau WYV

PROVIDER: S-EPMC9843249 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Pathogen-associated gene discovery workflows for novel antivirulence therapeutic development.

Lau Wing Yin Venus WYV Taylor Patrick K PK Brinkman Fiona S L FSL Lee Amy H Y AHY

EBioMedicine 20230109

Novel therapeutics to manage bacterial infections are urgently needed as the impact and prevalence of antimicrobial resistance (AMR) grows. Antivirulence therapeutics are an alternative approach to antibiotics that aim to attenuate virulence rather than target bacterial essential functions, while minimizing microbiota perturbation and the risk of AMR development. Beyond known virulence factors, pathogen-associated genes (PAGs; genes found only in pathogens to date) may play an important role in ...[more]

PMID: 36628845

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Project description:Classical Hodgkin lymphoma (cHL) is a common B-cell cancer and a significant health concern, especially in Western and Asian countries. Despite the effectiveness of chemotherapy, many relapse cases are being reported, highlighting the need for improved treatments. This study aimed to address this issue by discovering biomarkers through the analysis of gene expression data specific to cHL. Additionally, potential anticancer inhibitors were explored to target the discovered biomarkers. This study proceeded by retrieving microarray gene expression data from cHL patients, which was then analyzed to identify significant differentially expressed genes (DEGs). Functional and network annotation of the upregulated genes revealed the active involvement of matrix metallopeptidase 12 (MMP12) and C-C motif metallopeptidase ligand 22 (CCL22) genes in the progression of cHL. Additionally, the mentioned genes were found to be actively involved in cancer-related pathways, i.e., oxidative phosphorylation, complement pathway, myc_targets_v1 pathway, TNFA signaling via NFKB, etc., and showed strong associations with other genes known to promote cancer progression. MMP12, topping the list with a logFC value of +6.6378, was selected for inhibition using docking and simulation strategies. The known anticancer compounds were docked into the active site of the MMP12 molecular structure, revealing significant binding scores of -7.7 kcal/mol and -7.6 kcal/mol for BDC_24037121 and BDC_27854277, respectively. Simulation studies of the docked complexes further supported the effective binding of the ligands, yielding MMGBSA and MMPBSA scores of -78.08 kcal/mol and -82.05 kcal/mol for MMP12-BDC_24037121 and -48.79 kcal/mol and -49.67 kcal/mol for MMP12-BDC_27854277, respectively. Our findings highlight the active role of MMP12 in the progression of cHL, with known compounds effectively inhibiting its function and potentially halting the advancement of cHL. Further exploration of downregulated genes is warranted, as associated genes may play a role in cHL. Additionally, CCL22 should be considered for further investigation due to its significant role in the progression of cHL.

Dataset Information

Pathogen-associated gene discovery workflows for novel antivirulence therapeutic development.

Publications

Pathogen-associated gene discovery workflows for novel antivirulence therapeutic development.

Similar Datasets

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