Dataset Information

Linolenic Acid-Metronidazole: a Compound Relieving Drug Resistance and Inhibiting Helicobacter pylori.

ABSTRACT: Metronidazole (Met) is the first choice for treating Helicobacter pylori (Hp). However, Hp is easy to resistant, making Met unable to be widely used. How to overcome Hp's Met resistance is still an issue. In this study, Met was used as the primary raw material with linolenic acid to prepare a novel compound-linolenic acid-metronidazole (Lla-Met). The MIC, minimum bactericidal concentration (MBC), colonization amount of Hp in gastric mucosa, etc., were evaluated, respectively. Lla-Met was successfully prepared by the detection of nuclear magnetic resonance, etc., and its MIC and MBC to Hp were 2~4 μg/mL, 8~16 μg/mL. Moreover, in vivo experiments, Lla-Met significantly reduced the colonization of drug-resistant Hp in gastric mucosa. In the toxicity test, Lla-Met inhibited rate to GES-1 and BGC823 cells were 15% at 128 μg/mL; the mice were administered 10 times treatment Lla-Met treatment (240 mg/kg), have no difference significant injuries were found in their stomach, liver, spleen, kidney, and weight. In addition, Hp G27 continued for 18 days in vitro with sub-Lla-Met concentration, G27 did not show drug resistance to Lla-Met; Lla-Met did not exert an effect on non-Hp species with 128 μg/mL; Compared with a neutral environment, when the acid concentration is 3.0, Lla-Met is not decomposed and has better stability. Conclusion: Lla-Met, a newly prepared compound, has relatively well antibacterial of Met-resistant and sensitive Hp, with a capability of overcoming the metronidazole resistance of Hp.

SUBMITTER: Dai YY

PROVIDER: S-EPMC9295599 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Linolenic Acid-Metronidazole: a Compound Relieving Drug Resistance and Inhibiting Helicobacter pylori.

Dai Yuan-Yuan YY Qin Chun C Huang Gan-Rong GR Qin Yan-Chun YC Huang Yong-Yi YY Huang Yan-Qiang YQ Zhao Li-Juan LJ

Antimicrobial agents and chemotherapy 20220627 7

Metronidazole (Met) is the first choice for treating Helicobacter pylori (Hp). However, Hp is easy to resistant, making Met unable to be widely used. How to overcome Hp's Met resistance is still an issue. In this study, Met was used as the primary raw material with linolenic acid to prepare a novel compound-linolenic acid-metronidazole (Lla-Met). The MIC, minimum bactericidal concentration (MBC), colonization amount of Hp in gastric mucosa, etc., were evaluated, respe ...[more]

PMID: 35758720

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Project description:Efficacy of Helicobacter pylori (H. pylori) eradication therapy has declined due to rapid rises in antibiotic resistance. We investigated how increased temperature affected H. pylori (NCTC 11637) growth and its sensitivity to metronidazole in vitro. We performed transcriptomic profiling using RNA-sequencing to identify differentially expressed genes (DEGs) associated with increased temperature. Transcriptional pathways involved in temperature-driven metronidazole resistance changes were analyzed through bioinformatic and literature curation approaches. We showed that H. pylori growth was inhibited at 41°C and inhibition was more apparent with prolonged incubation. Resistance to metronidazole was also reduced-minimum inhibitory concentration for metronidazole decreased from > 256 μg/ml at 37°C to 8 μg/ml at 41°C after culturing for 3 days. RNA-sequencing results, which were highly concordant within treatment conditions, revealed more than one third of genes (583/1,552) to be differentially expressed at increased temperatures with similar proportions up and down-regulated. Quantitative real-time PCR validation for 8 out of 10 DEGs tested gave consistent direction in gene expression changes. We found enrichment for redox and oxygen radical pathways, highlighting a mechanistic pathway driving temperature-related metronidazole resistance. Independent literature review of published genes associated with metronidazole resistance revealed 46 gene candidates, 21 of which showed differential expression and 7 out of 9 DEGs associated with "redox" resistance pathways. Sanger sequencing did not detect any changes in genetic sequences for known resistance genes rdxA, frxA nor fdxB. Our findings suggest that temperature increase can inhibit the growth and reduce H. pylori resistance to metronidazole. Redox pathways are possible potential drivers in metronidazole resistance change induced by temperature. Our study provides insight into potential novel approaches in treating antibiotic resistant H. pylori.

Project description:Metronidazole (MNZ) is administered as first-line antibiotic for Helicobacter pylori eradication therapy; however, increasing resistance to MNZ impaired the efficacy. Increasing the dose of MNZ was recommended to overcome low-level resistance, but it was difficult to determine MNZ resistance level simply based on the rdxA gene mutation. In this study, the rdxA sequences of 511 clinical H. pylori strains were analyzed to assess the genotypes associated with MNZ resistance. We observed that the prevalences of rdxA sequences with missense, nonsense, and frameshift mutations were 70.25, 11.35, and 17.03%, respectively. Regarding the amino acid substitutions, T31E, H53R, D59N, L62V, S88P, G98S/N, R131K, and V172I were present in most strains regardless of the resistance phenotype. The correlation analysis showed R16H/C, Y47C, A67V/T, and V204I substitutions were associated with MNZ resistance. The mutation resulting in RdxA truncation was observed in 36.29% of the resistant strains, and 83.45% of these strains displayed high-level MNZ resistance (MIC > 256 μg/mL). Moreover, all strains with truncated mutation positions before amino acid 70 expressed high-level MNZ resistance. Our results indicated that most amino acid mutations probably contributed to the sequence diversity of RdxA, while R16H/C, Y47C, A67V/T, and V204I were potentially helpful to identify resistant strains. Although it was difficult to determine the mutations associated with MNZ resistance, the prediction of high-level resistance based on truncated characteristics of RdxA might be an important approach, which can effectively avoid H. pylori eradication therapy with unreasonable of MNZ dose increases for patients with high-level drug resistance. IMPORTANCE The increasing resistance to metronidazole impaired the efficacy of Helicobacter pylori eradication, and increasing the dose of metronidazole was recommended to overcome low-level resistance. For patients infected with highly resistant strains, the current empirical treatments, which generally used metronidazole in double doses or more, appeared impossibly to overcome the resistance and would only increase the incidence of adverse effects. Our results indicated that high-level metronidazole resistance was predominant, and almost half of the patients with high-level drug resistance could avoid usage of metronidazole based on the truncated mutations of RdxA sequences, which can effectively avoid H. pylori eradication therapy with unreasonable increases in the metronidazole dose.

Dataset Information

Linolenic Acid-Metronidazole: a Compound Relieving Drug Resistance and Inhibiting Helicobacter pylori.

Publications

Linolenic Acid-Metronidazole: a Compound Relieving Drug Resistance and Inhibiting Helicobacter pylori.

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