Abstract
Helicobacter pylori infects approximately half of the world population and is a major cause of gastritis, peptic ulcer, and gastric cancer. Moreover, this bacterium has quickly developed resistance to all major antibiotics. Recently, we developed a novel liposomal linolenic acid (LipoLLA) formulation, which showed potent bactericidal activity against several clinical isolated antibiotic-resistant strains of H. pylori including both the spiral and coccoid form. In addition, LipoLLA had superior in vivo efficacy compared to the standard triple therapy. Our data showed that LipoLLA associated with H. pylori cell membrane. Therefore, in this study, we investigated the possible antibacterial mechanism of LipoLLA against H. pylori. The antibacterial activity of LipoLLA (C18:3) was compared to that of liposomal stearic acid (LipoSA, C18:0) and oleic acid (LipoOA, C18:1). LipoLLA showed the most potent bactericidal effect and completely killed H. pylori within 5 min. The permeability of the outer membrane of H. pylori increased when treated with LipoOA and LipoLLA. Moreover, by detecting released adenosine triphosphate (ATP) from bacteria, we found that bacterial plasma membrane of H. pylori treated with LipoLLA exhibited significantly higher permeability than those treated with LipoOA, resulting in bacteria cell death. Furthermore, LipoLLA caused structural changes in the bacterial membrane within 5 min affecting membrane integrity and leading to leakage of cytoplasmic contents, observed by both transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Our findings showing rapid bactericidal effect of LipoLLA suggest it is a very promising new, effective anti-H. pylori agent.
Highlights
Helicobacter pylori is known to be associated with the pathogenesis of gastric diseases [1]
The liposome can fuse with bacterial membranes and directly release the entrapped Free Fatty acids (FFAs) molecules into bacterial membranes for efficient bactericidal activity as illustrated in Fig. 1C [12]
We examined morphological changes of H. pylori when treated with liposomal LLA (LipoLLA) for 5 min by scanning electron microscopy (SEM) and compared the images with transmission electron microscopy (TEM) images at higher magnification
Summary
Helicobacter pylori is known to be associated with the pathogenesis of gastric diseases [1]. Eradication of H. pylori is recommended for H. pylori associated diseases such as peptic ulcer disease, low grade gastric mucosa-associated lymphoid tissue lymphoma, and early gastric cancer, the success rate of eradication with standard therapy has decreased with increasing antimicrobial resistance to H. pylori [2,3]. Anti-H. pylori Action of Liposomal Linolenic Acid or concomitant therapy using different combinations of known antibiotics have been extensively studied, they have shown conflicting efficacy results and antibiotic resistance remains an unsolved problem [4]. A clinical study showed that orally ingested LLA did not inhibit the H. pylori colonization nor change the severity of H. pylori infection [15]
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