Aspects for development of novel antibacterial medicines using a vitamin D3 decomposition product in Helicobacter pylori infection.

A previous study by our group demonstrated that a vitamin D3 decomposition product (VDP1) acts as the selective bactericidal substance on Helicobacter pylori. VDP1 is an indene compound modified with a carbonyl and an alkyl. The alkyl of VDP1 turned out to be a mandatory structure to exert effective bactericidal action on H. pylori. Meanwhile, it still remains to be clarified as to how influence the alteration of the carbonyl in VDP1 has on the anti-H. pylori activity. In this study, we synthesized novel VDP1 derivatives that replaced the carbonyl of VDP1 by various functional groups and investigated the antibacterial action of the VDP1 derivatives on H. pylori. VDP1 derivatives retaining either a hydroxy (VD3-1) or an acetic ester (VD3-3) exhibited more effective bactericidal action to H. pylori than VDP1. The replacement of the carbonyl of VDP1 by either an allyl acetate (VD3-2) or an acrylic acid (VD3-5) provided almost no change to the anti-H. pylori activity. Apart from this, an isomer of VDP1 (VD3-4) slightly improved anti-H. pylori activity of VDP1. Meanwhile, the replacement of the carbonyl of VDP1 by a methyl acrylate (VD3-6) attenuated the anti-H. pylori activity. As with VDP1, its derivatives also were suggested to exert the anti-H. pylori action through the interaction with myristic acid side chains of dimyristoyl-phosphatidylethanolamine, a characteristic membrane lipid constituent of this pathogen. These results indicate that it is capable of developing specific antibacterial medicines for H. pylori targeting the biomembranal dimyristoyl-phosphatidylethanolamine using VDP1 as the fundamental structure.

Antibacterial effect of indene on Helicobacter pylori correlates with specific interaction between its compound and dimyristoyl-phosphatidylethanolamine.

Recent studies by our group have suggested that the vitamin D3 decomposition product VDP1 [(1R,3aR,7aR)-1-[(1R)-1,5-dimethylhexyl]octahydro-7a-methyl-4H-inden-4-one] confers the potent bactericidal action to Helicobacter pylori by targeting the membranal dimyristoyl-phosphatidylethanolamine (di-14:0 PE). In this study we synthesized a new VDP1 derivative to advance further investigation as for the correlative relationship between VDP1 structure and anti-H. pylori activity or PE vesicle collapse induction activity. The derivative VD3-7 [(1R,7aR)-4-fluoro-7a-methyl-1-((R)-6-methylheptan-2-yl)octahydro-1H-indene] retained a fluorine atom in place of the oxygen atom of VDP1. The fluorination of the carbonyl portion of VDP1 forfeited the effective anti-H. pylori activity. We, therefore, prepared Coomassie brilliant blue (CBB)-containing unilamellar vesicles consisting of various PE molecular species, and examined the vesicle collapse induction activity of either VDP1 or VD3-7 by detecting the CBB eluted from the PE unilamellar vesicles. VDP1 strongly induced CBB elution from the unilamellar vesicles of rectus-PE retaining the same two fatty acid side-chains shorter than carbon numbers 14, indicating that VDP1 specifically disrupted the vesicular conformation of those PE unilamellar vesicles. Meanwhile, VD3-7 had no influence on the structural stability of any PE unilamellar vesicles. This study obtained additional evidence that VDP1 acts as a bactericidal agent on H. pylori by targeting the membranal di-14:0 PE.