Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptomic analysis of Helicobacter pylori 26695 exposed to lethal concentration of a bactericidal inhibitor of the essential response regulator HsrA

ABSTRACT: Helicobacter pylori, a pathogenic member of phylum Campylobacterota (formerly Epsilonproteobacteria), is recognized as the leading cause of several human gastric pathologies, including acute and chronic gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. In the last two decades, the alarming increase of the antibiotic resistance levels to first-line and even “rescue” antibiotics, especially clarithromycin, metronidazole and levofloxacin, has led to a marked decrease of the eradication rates of traditional therapies. In previous works, we have validated the essential protein HsrA as an effective therapeutic target for H. pylori infection. HsrA is an OmpR/PhoB-type orphan response regulator, unique and highly conserved in members of phylum Campylobacterota, which appears involved in a variety of crucial physiological processes. In the present work, we carried out a transcriptomic analysis in order to discern the global effects of lethal concentrations of a bactericidal HsrA inhibitor on the H. pylori physiology. Treatment with the bactericidal HsrA inhibitor significantly changed the transcript levels of 367 open reading frames (ORF), of which 212 genes appeared upregulated and 155 genes resulted in downregulation, as compared with control samples. Thus, in vivo HsrA inhibition influenced, directly or indirectly, the expression of 23% of ORFs encoded by the H. pylori 26696 genome. Among the 268 differentially expressed genes (DEGs) with defined functions, two functional categories were highly enriched with downregulated genes involved in essential physiological processes: (1) ribosome biogenesis, and (2) electron transfer and oxidative phosphorylation.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Helicobacter pylori 26695

SUBMITTER: Irene Oliván Muro

PROVIDER: E-MTAB-14255 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Penicillins inhibit cell wall synthesis; therefore, H. pylori must be dividing for these antibiotics to be effective. Identifying growth responses to varying medium pH may allow design of more effective treatment regimens. Aim: To determine the effect of acidity on bacterial growth and the bactericidal efficacy of ampicillin. Methods: H. pylori were incubated in dialysis chambers suspended in 1.5L of media at various pHs with 5mM urea, with or without ampicillin, for 4, 8 or 16 hours, thus mimicking unbuffered gastric juice. Changes in gene expression, viability and survival were determined. The bacterial load of H. pylori infected gerbils was determined with and without profound acid inhibition. Results: At pH 3.0, but not at pH 4.5 or 7.4, there was decreased expression of ~400 genes, including many cell envelope biosynthesis, cell division genes and penicillin-binding proteins. In the presence of ampicillin, viability and survival declined at pH 4.5 and 7.4 but not at pH 3.0. Profound acid inhibition of H. pylori infected gerbils increased the antral bacterial load >3 fold, showing that elevation of intragastric pH stimulated growth. Conclusions: Ampicillin is bactericidal at pH 4.5 and 7.4, but not at pH 3.0, due to decreased expression of cell envelope and division genes at pH 3.0. Therefore, at pH 3.0, the pH at the gastric surface, the bacteria are non-dividing and persist with ampicillin treatment. A more effective inhibitor of acid secretion that maintains gastric pH near neutrality for 24 hours/day should enhance the efficacy of triple therapy and of amoxicillin, even allowing dual therapy for H. pylori eradication. There were a total of three biological replicates, each containing one control (incubated at pH 7.4) and one acidic (pH 3.0) sample, whose RNA were extracted on different dates. Microarray studies performed on these six samples were done in triplicate. One of the triplicates for two of the biological control triplicates were removed from the data set due to poor hybridization

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Transcriptomic analysis of Helicobacter pylori 26695 exposed to lethal concentration of a bactericidal inhibitor of the essential response regulator HsrA

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