Identifying potential novel drugs against Helicobacter pylori by targeting the essential response regulator HsrA

Scientific Reports
Andrés GonzálezÁngel Lanas

Abstract

The increasing antibiotic resistance evolved by Helicobacter pylori has alarmingly reduced the eradication rates of first-line therapies. To overcome the current circulating resistome, we selected a novel potential therapeutic target in order to identify new candidate drugs for treating H. pylori infection. We screened 1120 FDA-approved drugs for molecules that bind to the essential response regulator HsrA and potentially inhibit its biological function. Seven natural flavonoids were identified as HsrA binders. All of these compounds noticeably inhibited the in vitro DNA binding activity of HsrA, but only four of them, apigenin, chrysin, kaempferol and hesperetin, exhibited high bactericidal activities against H. pylori. Chrysin showed the most potent bactericidal activity and the most synergistic effect in combination with clarithromycin or metronidazole. Flavonoid binding to HsrA occurs preferably at its C-terminal effector domain, interacting with amino acid residues specifically involved in forming the helix-turn-helix DNA binding motif. Our results validate the use of HsrA as a novel and effective therapeutic target in H. pylori infection and provide molecular evidence of a novel antibacterial mechanism of some natural fla...Continue Reading

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Citations

Jan 14, 2020·Chinese Medical Journal·Yi HuNong-Hua Lu
Mar 14, 2020·International Journal of Molecular Sciences·Sandra Salillas, Javier Sancho
Aug 14, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Anna Duda-MadejEwa Dworniczek
Dec 19, 2019·Pharmaceutics·Andrés GonzálezÁngel Lanas
Mar 20, 2021·Emerging Topics in Life Sciences·Mahalakshmi Harish, Prasanna Venkatraman
Oct 15, 2020·Applied Microbiology and Biotechnology·Paula Roszczenko-JasińskaElżbieta K Jagusztyn-Krynicka
Aug 7, 2021·Frontiers in Cellular and Infection Microbiology·Andrés GonzálezÁngel Lanas
Aug 8, 2021·International Journal of Molecular Sciences·Annamaria ZannoniVincenzo Scarlato

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Methods Mentioned

BETA
X-ray
PCR
Protein Assay
Fluorescence
electrophoretic mobility shift
isothermal titration calorimetry
thermal shift

Software Mentioned

Origin
AutoDock Vina
AutoDock

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