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

Abstract

The increasing occurrence of multidrug-resistant strains of the gastric carcinogenic bacterium <i>Helicobacter pylori</i> 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 <i>H. pylori</i> by targeting the essential response regulator HsrA. To further evaluate the potential of 1,4-DHP as a scaffold for novel antimicrobials against <i>H. pylori</i>, 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 <i>H. pylori</i>, while at least one compound resulted as effective as metronidazole. Such antimicrobial actions appeared to be specific against <i>Epsilonproteobacteria</i>, since no deleterious effects were appreciated on <i>Escherichia coli</i> and <i>Staphylococcus epidermidis</i>. The new bactericidal DHP derivatives targeted the <i>H. pylori</i> regulator HsrA and inhibited its DNA binding activity according to both <i>in vitro</i> and <i>in vivo</i> analyses. Molecular docking predicted a potential druggable binding pocket in HsrA, which could open the door to structure-based design of novel anti-<i>H. pylori</i> drugs.