Dihydroorotate Dehydrogenase as a Target for the Development of Novel &lt;i&gt;Helicobacter pylori&lt;/i&gt;-Specific Antimicrobials

Ohishi, Tomokazu; Inaoka, Daniel Ken; Kita, Kiyoshi; Kawada, Manabu

doi:10.1248/cpb.c17-00796

Cited by 8 publications

(6 citation statements)

References 27 publications

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“…The increasing resistance to first-line antibiotic drugs, especially metronidazole and clarithromycin [55,56], has had a dramatic impact on the eradication rates, which have fallen to 70% in the last few years [1]. In order to overcome the antimicrobial resistance strategies evolved by this pathogen, novel molecular targets have emerged as candidates for therapeutic interventions [23,24,[57][58][59][60][61]. In a previous work, we validated a new effective anti-H. pylori therapeutic target, the essential response regulator HsrA [17].…”

Section: Discussionmentioning

confidence: 97%

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

et al. 2019

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Antibiotic resistance is a major cause of the increasing failures in the current eradication therapies against Helicobacter pylori. In this scenario, repurposing drugs could be a valuable strategy to fast-track novel antimicrobial agents. In the present study, we analyzed the inhibitory capability of 1,4-dihydropyridine (DHP) antihypertensive drugs on the essential function of the H. pylori response regulator HsrA and investigated both the in vitro antimicrobial activities and the in vivo efficacy of DHP treatments against H. pylori. Six different commercially available and highly prescribed DHP drugs—namely, Nifedipine, Nicardipine, Nisoldipine, Nimodipine, Nitrendipine, and Lercanidipine—noticeably inhibited the DNA binding activity of HsrA and exhibited potent bactericidal activities against both metronidazole- and clarithromycin-resistant strains of H. pylori, with minimal inhibitory concentration (MIC) values in the range of 4 to 32 mg/L. The dynamics of the decline in the bacterial counts at 2 × MIC appeared to be correlated with the lipophilicity of the drugs, suggesting different translocation efficiencies of DHPs across the bacterial membrane. Oral treatments with 100 mg/kg/day of marketed formulations of Nimodipine or Nitrendipine in combination with omeprazole significantly reduced the H. pylori gastric colonization in mice. The results presented here support a novel therapeutic solution for treatment of antibiotic-resistant H. pylori infections.

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Section: Discussionmentioning

confidence: 97%

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

et al. 2019

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“…DHODH inhibitors may have dual antiviral and immunoregulatory action by reducing the amount of pyrimidine available for viral replication in the host cell and by blocking cytokine release from immune cells . In addition, it would be meaningful to test the biological activities of indoluidin D and its derivatives against other types of DHODH derived from different species, such as Helicobacter pylori, Plasmodium falciparum, and other pathogens. , …”

Section: Discussionmentioning

confidence: 99%

“…Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in the de novo pyrimidine biosynthetic pathway. It is an attractive drug target for the treatment of various human diseases, such as rheumatoid arthritis and cancers, and the control of certain pathogens such as Plasmodium falciparum and Helicobacter pylori. − The DHODH family is categorized by sequence homology into classes 1 and 2, correlating with cellular localization and electron acceptor preference, respectively. Human DHODH belongs to class 2.…”

Section: Introductionmentioning

confidence: 99%

Identification of Dihydroorotate Dehydrogenase Inhibitors─Indoluidins─That Inhibit Cancer Cell Growth

et al. 2021

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Dihydroorotate dehydrogenase (DHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis and is a promising cancer treatment target. This study reports the identification of indoluidin D and its derivatives as inhibitors of DHODH. Cell-based phenotypic screening revealed that indoluidin D promoted myeloid differentiation and inhibited the proliferation of acute promyelocytic leukemia HL-60 cells. Indoluidin D also suppressed cell growth in various other types of cancer cells. Cancer cell sensitivity profiling with JFCR39 and proteomic profiling with ChemProteoBase revealed that indoluidin D is a DHODH inhibitor. Indoluidin D inhibited human DHODH activity in vitro; the DHODH reaction product orotic acid rescued indoluidin D-induced cell differentiation. We synthesized several indoluidin D diastereomer derivatives and demonstrated that stereochemistry was vital to their molecular activity. The indoluidin D derivative indoluidin E showed similar activity to its parent compound and suppressed tumor growth in a murine lung cancer xenograft model. Hence, indoluidin D and its derivatives selectively inhibit DHODH and suppress cancer cell growth.

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“…Indeed, it has been reported that the inhibition of complex III impairs the efficiency of pyrimidine de-novo biosynthesis [30]. Class 2 DHODHs are conserved in several pathogens, such as Helicobacter pylori [31,32], those causing fungal infections [33,34], Toxoplasma gondii [35], Plasmodium falciparum [37], and Schistosoma mansoni. [36] The ubiquinone binding site in human DHODH is known to be significantly divergent from its parasitic counterpart and several groups have reported the discovery of parasite-specific DHODH inhibitors (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Dihydroorotate dehydrogenase inhibitors in anti-infective drug research

Boschi

Pippione

Sainas

et al. 2019

European Journal of Medicinal Chemistry

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Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.

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Dihydroorotate Dehydrogenase as a Target for the Development of Novel <i>Helicobacter pylori</i>-Specific Antimicrobials

Cited by 8 publications

References 27 publications

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

Identification of Dihydroorotate Dehydrogenase Inhibitors─Indoluidins─That Inhibit Cancer Cell Growth

Dihydroorotate dehydrogenase inhibitors in anti-infective drug research

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