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Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

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Aragon Institute for Health Research (IIS Aragón), San Juan Bosco 13, 50009 Zaragoza, Spain
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Institute for Biocomputation and Physics of Complex Systems (BIFI), Mariano Esquilor (Edif. I+D), 50018 Zaragoza, Spain
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Department of Biochemistry and Molecular & Cellular Biology, University of Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain
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Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029 Madrid, Spain
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ARAID Foundation, Government of Aragon, Ranillas 1-D, 50018 Zaragoza, Spain
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Cancer Science Institute, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore
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UMR1053 Bordeaux Research in Translational Oncology, INSERM, Université Bordeaux, BaRITOn, 33000 Bordeaux, France
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French National Reference Center for Campylobacters & Helicobacters, 33000 Bordeaux, France
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Digestive Diseases Service, University Clinic Hospital Lozano Blesa; San Juan Bosco 15, 50009 Zaragoza, Spain
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Department of Medicine, Psychiatry and Dermatology, University of Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(12), 681; https://doi.org/10.3390/pharmaceutics11120681
Received: 20 November 2019 / Revised: 12 December 2019 / Accepted: 13 December 2019 / Published: 15 December 2019
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. View Full-Text
Keywords: repurposing; Helicobacter pylori; dihydropyridines; HsrA repurposing; Helicobacter pylori; dihydropyridines; HsrA
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González, A.; Casado, J.; Chueca, E.; Salillas, S.; Velázquez-Campoy, A.; Espinosa Angarica, V.; Bénejat, L.; Guignard, J.; Giese, A.; Sancho, J.; Lehours, P.; Lanas, Á. Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection. Pharmaceutics 2019, 11, 681.

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