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

IF 4.3 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Helicobacter Pub Date : 2024-04-14 DOI:10.1111/hel.13074

Sepideh Mofidifar, Abbas Yadegar, Mohammad Hossein Karimi-Jafari

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Abstract

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.

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重建幽门螺旋杆菌基因组尺度代谢模型，用于预测克拉霉素和利福平耐药性条件下的可能药物靶点

背景幽门螺旋杆菌被认为是一种真正的人类病原体，其耐药性的不断增加是全球范围内的一个严重问题。本研究旨在重建一个基因组规模的代谢模型（GSMM），以解读幽门螺杆菌菌株对克拉霉素和利福平的代谢能力，同时鉴定新的药物靶点。材料与方法根据基因组注释数据以及文献和数据库中的生化知识更新了幽门螺杆菌的 iIT341 模型。通过将克拉霉素和利福平耐药性的转录组数据整合到模型中，生成了针对特定环境的模型。通量平衡分析用于识别每个菌株中的重要基因，这些基因在与人类非同源、毒力因子分析、可药性和广谱分析的基础上被进一步优先排序。此外，还根据转录组数据的通量变异分析和通路富集分析，研究了敏感菌株和抗性菌株之间的代谢差异。结果重建的 GSMM 被命名为 HpM485 模型。通路富集和通量变异分析表明，克拉霉素耐药菌株和利福平耐药菌株的核糖体通路活性均有所降低。此外，耐克拉霉素菌株的代谢途径活性也明显下降。此外，在克拉霉素耐药菌株和利福平耐药菌株中分别检测到 23 个和 16 个必需基因。根据优先级分析，环丙烷脂肪酸合成酶和磷酸烯醇丙酮酸合成酶分别被确定为克拉霉素耐药菌株和利福平耐药菌株的潜在药物靶点。结论我们提出了一个稳健可靠的幽门螺杆菌代谢模型。该模型可预测新的药物靶点以对抗耐药性，并探索幽门螺杆菌在各种条件下的代谢能力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Helicobacter 医学-微生物学

CiteScore

8.40

自引率

9.10%

发文量

审稿时长

2 months

期刊介绍： Helicobacter is edited by Professor David Y Graham. The editorial and peer review process is an independent process. Whenever there is a conflict of interest, the editor and editorial board will declare their interests and affiliations. Helicobacter recognises the critical role that has been established for Helicobacter pylori in peptic ulcer, gastric adenocarcinoma, and primary gastric lymphoma. As new helicobacter species are now regularly being discovered, Helicobacter covers the entire range of helicobacter research, increasing communication among the fields of gastroenterology; microbiology; vaccine development; laboratory animal science.