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Luteolin as a urease inhibitor: a novel therapeutic strategy against Helicobacter pylori

ABSTRACT:

The rising prevalence of antibiotic-resistant Helicobacter pylori (H. pylori) underscores the urgent need for alternative treatment strategies. By producing ammonia to neutralize gastric acid, the key virulence factor urease is essential for H. pylori acid tolerance, thereby representing a promising therapeutic target. In this study, we identified luteolin as a potent urease inhibitor (IC50 = 30.50 μg/mL) from a screening of over 200 natural compounds. Further investigation through molecular docking, dynamics simulations, cellular thermal shift assay, and enzyme kinetics studies confirmed its competitive binding to the Ni2+-centered catalytic site of H. pylori urease (HPU). Luteolin exhibited potent anti-H. pylori activity under standard and simulated gastric conditions, and showed low propensity for resistance development over 14 serial passages. Proteomic and metabolomic analyses revealed that luteolin inhibited HPU activity, and the consequent ammonia restriction triggered severe metabolic dysfunction, characterized by disruptions in nucleotide, amino acid biosynthesis and TCA cycle. In GES-1 cells, luteolin protected against H. pylori-induced damage. In a mouse model of H. pylori-induced peptic ulcer, luteolin treatment significantly reduced the bacterial load, with concomitant alleviation of gastric mucosal pathology and suppression of inflammatory responses. In contrast to antibiotic-induced gastric microbial dysbiosis, microbial diversity analysis indicated that luteolin treatment had minimal impact on the resident gastric microbiota. In summary, as a urease inhibitor, luteolin suppresses H. pylori by blocking ammonia production, thereby disrupting acid neutralization and inducing metabolic dysfunction, which collectively alleviates gastric damage and inflammation while minimizing microbiota disruption and resistance risk.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS13581 | MetaboLights | 2026-02-28

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13581_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS13581_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13581_LC-MS_negative_hilic_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13581_LC-MS_positive_hilic_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:The human gastric pathogen Helicobacter pylori is extremely well adapted to the highly acidic conditions encountered in the stomach. The pronounced acid resistance of H. pylori relies mainly on the ammonia-producing enzyme urease, however, urease-independent mechanisms are likely to contribute to acid adaptation. Acid-responsive gene regulation is mediated at least in part by the ArsRS two-component system consisting of the essential OmpR-like response regulator ArsR and the non-essential cognate histidine kinase ArsS whose autophosphorylation is triggered in response to low pH. In this study by global transcriptional profiling of an ArsS-deficient H. pylori mutant grown at pH 5.0 we define the ArsR~P- dependent regulon consisting of 110 genes including the urease gene cluster, the genes encoding the aliphatic amidases AmiE and AmiF and the rocF gene encoding arginase. Transcriptome analyses were performed using a whole-genome microarray containing 1649 PCR products generated with specific primer pairs derived from the genome sequences of H. pylori 26695 (Tomb et al., 1997. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature 388:539-547) and J99 (Alm et al., 1999. Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature 397:176-180) which were spotted in duplicate. Microarrays were produced as described by Gressmann et al. (Gressmann et al., 2005. Gain and loss of multiple genes during the evolution of Helicobacter pylori. PLoS Genet 1(4):e43). To determine genes which are differentially expressed in the ArsS-deficient mutant G27/HP165::km at pH 5.0, cDNA was prepared from RNA extracted from H. pylori G27 and G27/HP165::km after exposing the bacteria for one hour to acidic pH. A total of eight RNA samples from two independent RNA preparations from strain G27 and G27/HP165::km, respectively, was used for cDNA labelling und hybridisation. Dye reversal colour swaps were performed as follows: One cDNA sample was generated using Cy3-dCTP and the other using Cy5-dCTP resulting in four labelled cDNAs per colour swap. Cy5-dCTP and Cy3-dCTP labelled cDNAs were combined and hybridized to the H. pylori microarray. The slides were scanned using ScanArray HT and analysed by using the ScanArray express software (Perkin Elmer). Spots were flagged and eliminated from analysis when the signal to background ratio was less then three or in obvious instances of high background or stray fluorescent signals. Median intensities of spots were background corrected and differences in dye bias were normalized by using the LOWESS algorithm (Yang et al., 2002. Normalization for cDNA microarray data: a robuste composite method addressing single and multiple slide systematic variation. Nucleic Acid Res. 30:e15). The signal ratios as measure of differential expression between the red and green channels were obtained from processed signal intensities. Ratios were further analysed with Microsoft Excel (Microsoft) and SAM software for statistic significance (Tusher et al., 2001. Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. USA 98:5116-5121). To determine the significance of differential expression RNA was isolated from the H. pylori G27 wild-type grown in BHI broth (pH 5.0), and 20 Âµg of this RNA were labelled either with Cy3-dCTP or with Cy5-dCTP. The two cDNA probes generated were hybridized onto the same slide, and the data were analysed as mentioned above. Signal ratios < 0.5 and > 2.0 were analyzed further.

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Luteolin as a urease inhibitor: a novel therapeutic strategy against Helicobacter pylori

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