Vitamin K2 in Electron Transport System: Are Enzymes Involved in Vitamin K2 Biosynthesis Promising Drug Targets?

Kurosu, Masaaki; Eeshwaraiah, B.

doi:10.3390/molecules15031531

Cited by 135 publications

(140 citation statements)

References 105 publications

(107 reference statements)

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“…CZM, and to some extent BDQ, thus behave similarly to Ro48-8071, a lipophilic amine inhibitor of MenA, whose activity was partly suppressed by 400 M MK-4 (21). However, the antagonistic effect of MK-4 against CZM activity may not be of clinical relevance, as the concentrations used in the present work exceed the physiological levels in humans (22).…”

Section: Figmentioning

confidence: 98%

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

Lechartier

Cole

2015

Antimicrob Agents Chemother

117

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Clofazimine (CZM) is an antileprosy drug that was recently repurposed for treatment of multidrug-resistant tuberculosis. In Mycobacterium tuberculosis, CZM appears to act as a prodrug, which is reduced by NADH dehydrogenase (NDH-2), to release reactive oxygen species upon reoxidation by O 2 . CZM presumably competes with menaquinone (MK-4), a key cofactor in the mycobacterial electron transfer chain, for its reduction by NDH-2. We studied the effect of MK-4 supplementation on the activity of CZM against M. tuberculosis and found direct competition between CZM and MK-4 for the cidal effect of CZM, against nonreplicating and actively growing bacteria, as MK-4 supplementation blocked the drug's activity against nonreplicating bacteria. We demonstrated that CZM, like bedaquiline, is synergistic in vitro with benzothiazinones such as 2-piperazino-benzothiazinone 169 (PBTZ169), and this synergy also occurs against nonreplicating bacteria. The synergy between CZM and PBTZ169 was lost in an MK-4-rich medium, indicating that MK-4 is the probable link between their activities. The efficacy of the dual combination of CZM and PBTZ169 was tested in vivo, where a great reduction in bacterial load was obtained in a murine model of chronic tuberculosis. Taken together, these data confirm the potential of CZM in association with PBTZ169 as the basis for a new regimen against drug-resistant strains of M. tuberculosis. With approximately 9 million incident cases of tuberculosis (TB) worldwide and around 1.5 million deaths in 2012, Mycobacterium tuberculosis infection is one of the most important causes of death from a single infectious agent (1). The spread of multidrug-resistant TB (MDR-TB), namely, with resistance to isoniazid and rifampin, poses additional challenges to treatment with currently available anti-TB drugs. The situation is exacerbated by the increasing emergence of extensively drug-resistant (XDR) strains of M. tuberculosis, which cause diseases essentially untreatable with existing compounds. It is nowadays widely acknowledged that we need to develop new antibiotic combinations for TB and that these new regimens should be tested together at the preclinical stage, rather than testing a series of single drugs separately, in order to fill the TB drug development pipeline more efficiently (2-4).Some of the compounds in advanced clinical trials for TB are molecules that were originally used to treat other infectious diseases and have been repurposed for TB. Among the repurposed molecules, clofazimine (CZM), a riminophenazine originally developed as a drug to treat TB but overlooked for decades, has been used as a standard component of the treatment of leprosy for 50 years. It was recently repurposed for managing MDR-TB cases, notably following the results of the so-called Bangladesh study, which demonstrated that a CZM-containing regimen can cure such resistant cases in 9 to 12 months (5). Grosset et al. demonstrated the substantial benefit of adding CZM to second-line regimens in mice infected with isoniazid-resistant...

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Section: Figmentioning

confidence: 98%

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

Lechartier

Cole

2015

Antimicrob Agents Chemother

117

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“…Quinones are lipid-soluble electron carriers essential to cellular respiration in bacteria (1). Although certain bacteria (e.g.…”

mentioning

confidence: 99%

Structural and Biochemical Characterization of Chlamydia trachomatis Hypothetical Protein CT263 Supports That Menaquinone Synthesis Occurs through the Futalosine Pathway

Barta

Thomas

Yuan

et al. 2014

Journal of Biological Chemistry

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Background: Specific pathways and components for respiration in Chlamydia are poorly understood. Results: The C. trachomatis hypothetical protein CT263 crystal structure displays strong structural similarity with 5Ј-methylthioadenosine nucleosidase enzymes. Conclusion: Bioinformatic analyses and enzymatic characterization of CT263 suggest menaquinone biosynthesis proceeds through the futalosine pathway in Chlamydiaceae. Significance: Unique structural aspects of the CT263 active site can be leveraged to modify existing transition state inhibitors.

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“…These quinones are important for the respiratory chain and play vital roles in cellular respiration, oxidative phosphorylation and formation of transmembrane potential in bacteria (3). Some bacteria have more than one of these quinones which they utilize according to growth conditions (4).…”

Section: Menaquinone Its Role and Distributionmentioning

confidence: 99%

Menaquinone as a potential target of antibacterial agents

Paudel

Hamamoto

Panthee

et al. 2016

DD&T

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Vitamin K2 in Electron Transport System: Are Enzymes Involved in Vitamin K2 Biosynthesis Promising Drug Targets?

Cited by 135 publications

References 105 publications

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

Mode of Action of Clofazimine and Combination Therapy with Benzothiazinones against Mycobacterium tuberculosis

Structural and Biochemical Characterization of Chlamydia trachomatis Hypothetical Protein CT263 Supports That Menaquinone Synthesis Occurs through the Futalosine Pathway

Menaquinone as a potential target of antibacterial agents

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