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

• Published in: Scientific reports 2019-08, Vol.9 (1), p.11294-13, Article 11294
• Main Authors: González, Andrés, Salillas, Sandra, Velázquez-Campoy, Adrián, Espinosa Angarica, Vladimir, Fillat, María F., Sancho, Javier, Lanas, Ángel
• Format: Article
• Language: English
• Subjects: 119/118; 631/154/1435/2163; 631/92/507; 82/16; 82/29; 82/80; 82/83; Amino acids; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Bacterial Proteins - antagonists & inhibitors; Bacterial Proteins - metabolism; Bactericidal activity; Binders; Clarithromycin; Deoxyribonucleic acid; DNA; Drug development; Drug Discovery; Drugs; Eradication; Flavonoids; Flavonoids - chemistry; Flavonoids - pharmacology; Helicobacter Infections - drug therapy; Helicobacter Infections - microbiology; Helicobacter pylori; Helicobacter pylori - drug effects; Helicobacter pylori - metabolism; Hesperidin; Humanities and Social Sciences; Humans; Kaempferol; Metronidazole; Molecular Docking Simulation; multidisciplinary; Science; Science (multidisciplinary); Synergistic effect; Therapeutic applications
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-47746-9

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 flavonoids against H . pylori . The results further support the valuable potential of natural flavonoids as candidate drugs for novel antibacterial strategies.