A reconstructed genome-scale metabolic model of Helicobacter pylori for predicting putative drug targets in clarithromycin and rifampicin resistance conditions.

BACKGROUND: Helicobacter pylori is considered a true human pathogen for which rising drug resistance constitutes a drastic concern globally. The present study aimed to reconstruct a genome-scale metabolic model (GSMM) to decipher the metabolic capability of H. pylori strains in response to clarithromycin and rifampicin along with identification of novel drug targets. MATERIALS AND METHODS: The iIT341 model of H. pylori was updated based on genome annotation data, and biochemical knowledge from literature and databases. Context-specific models were generated by integrating the transcriptomic data of clarithromycin and rifampicin resistance into the model. Flux balance analysis was employed for identifying essential genes in each strain, which were further prioritized upon being nonhomologs to humans, virulence factor analysis, druggability, and broad-spectrum analysis. Additionally, metabolic differences between sensitive and resistant strains were also investigated based on flux variability analysis and pathway enrichment analysis of transcriptomic data. RESULTS: The reconstructed GSMM was named as HpM485 model. Pathway enrichment and flux variability analyses demonstrated reduced activity in the ribosomal pathway in both clarithromycin- and rifampicin-resistant strains. Also, a significant decrease was detected in the activity of metabolic pathways of clarithromycin-resistant strain. Moreover, 23 and 16 essential genes were exclusively detected in clarithromycin- and rifampicin-resistant strains, respectively. Based on prioritization analysis, cyclopropane fatty acid synthase and phosphoenolpyruvate synthase were identified as putative drug targets in clarithromycin- and rifampicin-resistant strains, respectively. CONCLUSIONS: We present a robust and reliable metabolic model of H. pylori. This model can predict novel drug targets to combat drug resistance and explore the metabolic capability of H. pylori in various conditions.

Repurposing existing drugs for new AMPK activators as a strategy to extend lifespan: a computer-aided drug discovery study.

Dietary restriction is one of the several ways which could putatively extend organisms' lifespan, ranging from Saccharomyces cerevisiae to rodents, by activating the AMP-activated protein kinase (AMPK), an ATP/AMP sensor. Extensive researches have shown that aging reduces sensibility of AMPK and eventually causes energy imbalance in cells. Research in mammals' AMPK depicts that this signaling molecule could control autophagy, improve cellular stress resistance and suppress inflammatory responses. Hence, in this study we performed a drug repurposing of 1908 FDA-approved drugs in order to discover putative safe activators of AMPK and to find new applications for existing drugs. For this purpose, FDA-approved drugs were screened by virtual screening and the ligand-protein interactions were carefully inspected. Moreover, through MM/PBSA analysis, the binding affinity of hit compounds in γ and αß binding sites were investigated. As Cangrelor, Nacitentan, Levoleucovorin and Glisoxepide had lower binding affinities; we predicted that they would probably prove to be more potential activators than C2. However, hit-compounds in αß binding site, exhibited higher unfavorable binding affinity. Hence, present findings can prove to be valuable for discovering new activators for AMPK.