Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

Abstract

Antibiotic resistance is a major cause of the increasing failures in the current eradication therapies against <i>Helicobacter pylori</i>. 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 <i>H. pylori</i> response regulator HsrA and investigated both the in vitro antimicrobial activities and the in vivo efficacy of DHP treatments against <i>H. pylori</i>. 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 <i>H. pylori</i>, 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 <i>H. pylori</i> gastric colonization in mice. The results presented here support a novel therapeutic solution for treatment of antibiotic-resistant <i>H. pylori</i> infections.