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Helicobacter pylori has developed antimicrobial resistance to virtually all current antibiotics. Thus, there is a pressing need to develop new anti-H. pylori therapies. We recently described a novel oligo-acyl-lysyl (OAK) antimicrobial peptidomimetic, C12 K-2β12 , that shows potentin vitro bactericidal activity againstH. pylori . Herein, we define the mechanism of action and evaluate thein vivo efficacy of C12 K-2β12 againstH. pylori after experimental infection of Mongolian gerbils. We demonstrate using a 1-N -phenylnaphthylamine (fluorescent probe) uptake assay and electron microscopy that C12 K-2β12 rapidly permeabilizes the bacterial membrane and creates pores that cause bacterial cell lysis. Furthermore, using nucleic acid binding assays, Western blots, and confocal microscopy, we show that C12 K-2β12 can cross the bacterial membranes into the cytoplasm and tightly bind to bacterial DNA, RNA, and proteins, a property that may result in inhibition of enzymatic activities and macromolecule synthesis. To define thein vivo efficacy of C12 K-2β12 ,H. pylori -infected gerbils were orogastrically treated with increasing doses and concentrations of C12 K-2β12 1 day or 1 week postinfection. The efficacy of C12 K-2β12 was strongest in animals that received the largest number of doses at the highest concentration, indicating dose-dependent activity of the peptide (P &lt; 0.001 by analysis of variance [ANOVA]) regardless of the timing of the treatment with C12 K-2β12 . Overall, our results demonstrate a dual mode of action of C12 K-2β12 against theH. pylori membrane and cytoplasmic components. Moreover, and consistent with the previously reportedin vitro efficacy, C12 K-2β12 shows significantin vivo efficacy againstH. pylori when used as monotherapy. Therefore, OAK peptides may be a valuable resource for therapeutic treatment ofH. pylori infection.

antimicrobial agents and chemotherapy

The Oligo-Acyl Lysyl Antimicrobial Peptide C 12 K-2β 12 Exhibits a Dual Mechanism of Action and Demonstrates Strong In Vivo Efficacy against Helicobacter pylori