Repurposing dihydropyridines for treatment of helicobacter pylori infection

González, Andrés (Universidad de Zaragoza) ; Casado, Javier ; Chueca, Eduardo ; Salillas, Sandra (Universidad de Zaragoza) ; Velázquez-Campoy, Adrián (Universidad de Zaragoza) ; Espinosa Angarica, Vladimir ; Bénejat, Lucie ; Guignard, Jérome ; Giese, Alban ; Sancho, Javier (Universidad de Zaragoza) ; Lehours, Philippe ; Lanas, Ángel (Universidad de Zaragoza)

Resumen: Antibiotic resistance is a major cause of the increasing failures in the current eradication therapies against Helicobacter pylori. In this scenario, repurposing drugs could be a valuable strategy to fast-track novel antimicrobial agents. In the present study, we analyzed the inhibitory capability of 1, 4-dihydropyridine (DHP) antihypertensive drugs on the essential function of the H. pylori response regulator HsrA and investigated both the in vitro antimicrobial activities and the in vivo efficacy of DHP treatments against H. pylori. Six different commercially available and highly prescribed DHP drugs—namely, Nifedipine, Nicardipine, Nisoldipine, Nimodipine, Nitrendipine, and Lercanidipine—noticeably inhibited the DNA binding activity of HsrA and exhibited potent bactericidal activities against both metronidazole-and clarithromycin-resistant strains of H. pylori, with minimal inhibitory concentration (MIC) values in the range of 4 to 32 mg/L. The dynamics of the decline in the bacterial counts at 2 × MIC appeared to be correlated with the lipophilicity of the drugs, suggesting different translocation efficiencies of DHPs across the bacterial membrane. Oral treatments with 100 mg/kg/day of marketed formulations of Nimodipine or Nitrendipine in combination with omeprazole significantly reduced the H. pylori gastric colonization in mice. The results presented here support a novel therapeutic solution for treatment of antibiotic-resistant H. pylori infections.

Idioma: Inglés

DOI: 10.3390/pharmaceutics11120681

Año: 2019

Publicado en: Pharmaceutics 11, 12 (2019), 681 [18 pp.]
ISSN: 1999-4923

Factor impacto JCR: 4.421 (2019)

Categ. JCR: PHARMACOLOGY & PHARMACY rank: 44 / 270 = 0.163 (2019) - Q1 - T1

Factor impacto SCIMAGO: 0.894 - Pharmaceutical Science (Q1)

Financiación: info:eu-repo/grantAgreement/ES/CI2017-001-3
Financiación: info:eu-repo/grantAgreement/ES/DGA/B25
Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-17R
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI11-02578
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/FJCI-2014-20704
Financiación: info:eu-repo/grantAgreement/ES/MINECO/IJCI-2016-27419

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)