Bacteriolytic action of vitamin D3 and its derivatives against
Abstract
Helicobacter pylori is one of the most prevalent causes of gastritis. This pathogen colonizes for many years human stomach and asymptomatically leads the persons to chronic gastritis. The eradication of H. pylori from human stomach is, therefore, important in order to prevent the digestive diseases including peptic ulcers and gastric cancer that develop via chronic atrophic gastritis. Wide-spectrum antibiotics such as amoxicillin and metronidazole are used for the treatment for H. pylori infectious diseases. However, the H. pylori strains resistant to these antibiotics are increasing year by year around the world. On this basis, we need urgently to develop the antibacterial medicines that act on H. pylori with a novel mechanism. Recent studies by our group have demonstrated that H. pylori shows susceptibility to the bactericidal action of indene compounds derived from decomposition of vitamin D. The bactericidal action of indene compounds is selective not against commonplace bacteria but against H. pylori. The indene compounds turned out to target the H. pylori’s phosphatidylethanolamine that retains a myristic acid as the saturated fatty acid side chain. These findings will contribute to the development of new antibacterial medicines specialized to the treatment for H. pylori infectious diseases.
Keywords
- Helicobacter pylori
- phosphatidylethanolamine
- myristic acid
- vitamin D
- indene compound
1. Introduction
The assimilation of exogenous cholesterol into the cell membranes is one of the unique biological features of
A number of studies, including our own, have revealed that
Based on a number of studies including our own, the overview from the cholesterol assimilation to the cholesterol glucosylation was partially clarified in
As described above, it has been revealed that DMPE is one of the most prevalent lipid components of
2. Development of new antibacterial medicines for H. pylori
2.1 Finding of an indene compound as the anti-H. pylori substance
The anti-
2.2 Interaction between VDP1 and PE molecular species
The collapse induction activity of VDP1 against lipid vesicles was next examined using the unilamellar vesicles prepared with DMPE, dipalmitoyl-PE (DPPE), and dioleoyl-PE (DOPE). Intriguingly, VDP1 turned out to specifically induce the structure collapse of DMPE unilamellar vesicles without affecting the structural stability of either DPPE unilamellar vesicles or DOPE unilamellar vesicles (Figure 5). The structure collapse induction activity of VDP1 against DMPE unilamellar vesicles completely corresponded to the bactericidal activity of the indene compound against
The intermolecular interaction between VDP1, DMPE, and DPPE was, therefore, simulated by the computational chemistry. One of the computer simulations showed that VDP1 induces “the winding-structure change” to a myristic acid side chain in DMPE molecule, while VDP1 induced no structure change to a palmitic acid side chain in DPPE molecule (Figure 5). The alkyl of VDP1 seemed to be crucial conformation for the induction of the structure change of the myristic acid side chain of DMPE. In other words, the slight difference of the length of carbon chain composing the fatty acids in PE molecules appeared to play an important role on the specific interaction between VDP1 and PE molecular species.
2.3 Bactericidal mechanism of the indene compound species
As described earlier, VDP1 was considered to confer the bacteriolytic action to
A recent study by our group has demonstrated that VDP1 confers the antibacterial action not only to
In contrast,
Based on the current studies, the following bactericidal mechanism of the indene compounds synthetically derived from vitamin D in
In the case of the cholesterol assimilation in
3. Conclusions
Almost all hydrophobic drugs are pharmacologically designed to inhibit the functions of either protein molecules or nucleic acids in the target creature species. However, no drugs that target a characteristic lipid molecule in the creatures are discovered for many years. In addition, a number of biochemists on lipid research leave great achievements in the analysis of biosynthetic enzymes of various lipophilic compounds such as fatty acids and complex lipids and in the identification of receptors of various hydrophobic ligands such as steroid hormones and eicosanoids. However, these achievements are not as for lipid itself but as for merely proteins. This chapter described the unique interaction between lipids: the indene compound species specifically disrupt the vesicular conformation consisting of DMPE. These findings will bring the new aspects to the drug discovery research and the lipid biochemistry research.
Acknowledgments
This work was supported by a Grant-in-Aid from the Adaptable and Seamless Technology Transfer Program through Target-Driven R&A (A-STEP), JSPS KAKENHI (grant number 15 K08006), and JKA promotion funds from KEIRIN RACE.
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