1,4-Dihydropyridine as a Promising Scaffold for Novel Antimicrobials Against Helicobacter pylori

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Gonzalez A., Casado J., Gunduz M. G., Santos B., Velazquez-Campoy A., Sarasa-Buisan C., ...Daha Fazla

FRONTIERS IN MICROBIOLOGY, cilt.13, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 13
  • Basım Tarihi: 2022
  • Doi Numarası: 10.3389/fmicb.2022.874709
  • Dergi Adı: FRONTIERS IN MICROBIOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, EMBASE, Veterinary Science Database, Directory of Open Access Journals
  • Anahtar Kelimeler: Helicobacter pylori, HsrA, hexahydroquinoline, novel antimicrobial drugs, antibiotic resistance, dihydropyridine, RESPONSE REGULATOR HP1043, IN-VITRO EVALUATION, BIOLOGICAL EVALUATION, MEDICINAL CHEMISTRY, DERIVATIVES, ANTIBACTERIAL, DESIGN, EXPRESSION, DISCOVERY, DOCKING
  • Hacettepe Üniversitesi Adresli: Evet

Özet

The increasing occurrence of multidrug-resistant strains of the gastric carcinogenic bacterium Helicobacter pylori threatens the efficacy of current eradication therapies. In a previous work, we found that several 1,4-dihydropyridine (DHP)-based antihypertensive drugs exhibited strong bactericidal activities against H. pylori by targeting the essential response regulator HsrA. To further evaluate the potential of 1,4-DHP as a scaffold for novel antimicrobials against H. pylori, we determined the antibacterial effects of 12 novel DHP derivatives that have previously failed to effectively block L- and T-type calcium channels. Six of these molecules exhibited potent antimicrobial activities (MIC <= 8 mg/L) against three different antibiotic-resistant strains of H. pylori, while at least one compound resulted as effective as metronidazole. Such antimicrobial actions appeared to be specific against Epsilonproteobacteria, since no deleterious effects were appreciated on Escherichia coli and Staphylococcus epidermidis. The new bactericidal DHP derivatives targeted the H. pylori regulator HsrA and inhibited its DNA binding activity according to both in vitro and in vivo analyses. Molecular docking predicted a potential druggable binding pocket in HsrA, which could open the door to structure-based design of novel anti-H. pylori drugs.