In Vitro and In Vivo Activities of Zinc Linolenate, a Selective Antibacterial Agent against Helicobacter pylori

Abstract

Helicobacter pylori is a major global pathogen, and its infection represents a key factor in the etiology of various gastric diseases, including gastritis, peptic ulcers, and gastric carcinoma. The efficacy of current standard treatment for H. pylori infection including two broad-spectrum antibiotics is compromised by toxicity toward the gut microbiota and the development of drug resistance, which will likely only be resolved through novel and selective antibacterial strategies. Here, we synthesized a small molecule, zinc linolenate (ZnLla), and investigated its therapeutic potential for the treatment of H. pylori infection. ZnLla showed effective antibacterial activity against standard strains and drug-resistant clinical isolates of H. pylori in vitro with no development of resistance during continuous serial passaging. The mechanisms of ZnLla action against H. pylori involved the disruption of bacterial cell membranes and generation of reactive oxygen species. In mouse models of multidrugresistant H. pylori infection, ZnLla showed in vivo killing efficacy comparable and superior to the triple therapy approach when use as a monotherapy and a combined therapy with omeprazole, respectively. Moreover, ZnLla treatment induces negligible toxicity against normal tissues and causes minimal effects on both the diversity and composition of the murine gut microbiota. Thus, the high degree of selectivity of ZnLla for H. pylori provides an attractive candidate for novel targeted anti-H. pylori treatment.

Transformation of Helicobacter pylori into Coccoid Forms as a Challenge for Research Determining Activity of Antimicrobial Substances

“…The decrease in viability was seen after 48-h exposure to MBC (a 4-log reduction). The next article [65] noted a rapid decrease in the number of viable cells (a total bacterial destruction after 70 min with MIC of zinc linolenate), which was associated with a reduction in intracellular ATP, increase in the permeability of cellular membranes, vesiculation, and spherical forms appearance. In the last analyzed study [43], it was observed that the morphology of H. pylori affected the parameters required to kill the cells of this bacterium.…”

“…In four articles [43,[63][64][65] determining the effect of fatty acids and fatty acid derivatives on H. pylori, one research used microscopy and culture methods demonstrating a bacteriostatic nature of the tested compound [63], while other three studies were expanded to include fluorescent or molecular methods, and here the activity of the compounds was interpreted as bactericidal [43,64,65] ( Table 4 and Figure 4).…”

“…The remaining three included articles [43,64,65] suggested an existence of bactericidal properties of the compounds. Yonezawa et al [64] noted that a 24-h incubation with MBC of sodium butyrate stimulated an appearance of spherical forms and accompanied release of membrane vesicles and eDNA.…”

“…The heterogeneity of the results of the research presented in this review makes it difficult to clearly judge this issue. Based on a comparison of the level of bactericidal activity, speed of action, and an ability to act on both morphological forms of H. pylori (spiral and coccoid), one can be tempted to select representatives from each group of compounds: essential oils [46] and propolis components [54] (plant compounds); SQ109 [62], 3-bromopyruvate [40] and sertraline [41] (synthetic compounds); linolenic acid and its derivatives [43,65] (fatty acids), and (PGA) m -r-(PHLG-MHH) n [68] (peptides). It is suggested that promising results obtained in vitro for planktonic H. pylori forms for these substances should be verified in vivo and for biofilm forms of these bacteria.…”

Broad-Spectrum Antiviral Natural Products from the Marine-Derived Penicillium sp. IMB17-046

“…The antibacterial activities against H. pylori , S. aureus , B. subtilis , P. aeruginosa, and K. pneumonia were assayed by examining the MIC using the broth micro-dilution method as previously described [5,35].…”