Identification of Mannich Base as a Novel Inhibitor of <i>Mycobacterium Tuberculosis</i> Isocitrate by High-Throughput Screening

Ji, Lei; Long, Quanxin; Yang, De-Qian; Xie, Jianping

doi:10.7150/ijbs.7.376

Cited by 28 publications

(16 citation statements)

References 21 publications

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“…Targeting vital metabolic pathways of dormant mycobacteria not present in mammalian cells is an obvious strategy. Isocitrate lyase, a key enzyme in the glyoxylate bypass pathway, is an attractive option although thus far efforts to target this enzyme have proven difficult[51]. One of the primary difficulties encountered by the bacillus in adapting to hypoxia is in disposing of excess reducing equivalents generated by both anabolic and catabolic processes [52].…”

Section: Targeting Dormant Mycobacteriamentioning

confidence: 99%

Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies

Esmail

Barry²,

Wilkinson

2012

Drug Discovery Today

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Treatment of latent tuberculosis (LTBI) is a vital component of tuberculosis elimination but is not efficiently implemented with available diagnostics and therapeutics. The tuberculin skin test and interferon gamma release assays can inform that infection has occurred but do not prove that it persists. Treatment of LTBI with isoniazid targets actively replicating bacilli but not non-replicating populations, prolonging treatment duration. Developing more predictive diagnostic tests and treatments of shorter duration requires a greater understanding of the biology of latent tuberculosis, from both host and bacillary perspectives. In this article we discuss the basis of current diagnosis and treatment of LTBI and review recent developments in understanding the biology of latency that may enable future improved diagnostic and treatment strategies.

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Section: Targeting Dormant Mycobacteriamentioning

confidence: 99%

Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies

Esmail

Barry²,

Wilkinson

2012

Drug Discovery Today

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“…Other than derivative synthesis, other categories of synthetic compound such as DNAzymes [ 41 ], Mannich bases [ 42 ], peptide inhibitors [ 43 , 44 ], and pyruvate-isoniazid analog with their copper complex [ 45 ] also gained some attention in the crowd. In 2005, the concept of silencing the icl gene by DNAzymes was introduced.…”

Section: Discovery Of Isocitrate Lyase Potential Inhibitors From Dmentioning

confidence: 99%

Potential Inhibitors for Isocitrate Lyase ofMycobacterium tuberculosisand Non-M. tuberculosis: A Summary

Lee

Wahab

Choong

2015

BioMed Research International

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Isocitrate lyase (ICL) is the first enzyme involved in glyoxylate cycle. Many plants and microorganisms are relying on glyoxylate cycle enzymes to survive upon downregulation of tricarboxylic acid cycle (TCA cycle), especially Mycobacterium tuberculosis (MTB). In fact, ICL is a potential drug target for MTB in dormancy. With the urge for new antitubercular drug to overcome tuberculosis treat such as multidrug resistant strain and HIV-coinfection, the pace of drug discovery has to be increased. There are many approaches to discovering potential inhibitor for MTB ICL and we hereby review the updated list of them. The potential inhibitors can be either a natural compound or synthetic compound. Moreover, these compounds are not necessary to be discovered only from MTB ICL, as it can also be discovered by a non-MTB ICL. Our review is categorized into four sections, namely, (a) MTB ICL with natural compounds; (b) MTB ICL with synthetic compounds; (c) non-MTB ICL with natural compounds; and (d) non-MTB ICL with synthetic compounds. Each of the approaches is capable of overcoming different challenges of inhibitor discovery. We hope that this paper will benefit the discovery of better inhibitor for ICL.

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“…3d) were found to be the most potent inhibitors, with the inhibition constants (K i ) of 120, 190, 120, and 3 μM, respectively. In another study, IC 50 (the half maximal inhibitory concentration) of oxalate was determined as 0.013 M [41]. Oxalate and malate were also shown to suppress isocitrate lyase activity to approximately 50% at the concentration of 5 mM [53].…”

Section: Structural Analogues Of Metabolic Intermediates Ionsmentioning

confidence: 99%

“…Isocitrate lyase has been reported as one of the essential enzymes responsible for the growth of M. tuberculosis in activated macrophages and persistence in macrophages [40,41]. It has also been found that icl gene is vital for survival of M. tuberculosis in the lungs of infected mice during the persistent phase of infection (2-16 weeks), but it is not essential during the early and acute phase (0-2 weeks) of infection [40].…”

Section: Introductionmentioning

confidence: 99%

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Advances in Mycobacterial Isocitrate Lyase Targeting and Inhibitors

Krátký¹,

Vinšová²

2012

Current Medicinal Chemistry

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Isocitrate lyase plays a key role for survival of Mycobacterium tuberculosis in the latent form during a chronic stage of infection. This enzyme is important for M. tuberculosis during steady stage growth when it converts isocitrate to succinate and glyoxylate. Then, the glyoxylate is condensed with acetyl-CoA to form malate by malate synthase. The carbon conserving glyoxylate pathway has not been observed in mammals; therefore, it has been determined as a potential drug target for discovery of a new antituberculosis agent. Novel active molecules should shorten the duration of therapy, prevent resistance development and eliminate latent disease. The review summarizes recent progresses in isocitrate lyase inhibitors, overviews structural analogues of several metabolic intermediates (3-nitropropionate, 3-bromopyruvate, itaconate, itaconic anhydride), peptide inhibitors, and recently developed inhibitors with various chemical structures. The largest inhibitory activity against isocitrate lyase (IC(50) of 0.10 ± 0.01 μM) and concomitantly a significant antimycobacterial activity has been presented by fluoroquinolone derivative 1-cyclopropyl-7-[3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which has incorporated 3-nitropropionyl group as one of the structural analogue of succinate, a metabolic intermediate.

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Identification of Mannich Base as a Novel Inhibitor of Mycobacterium Tuberculosis Isocitrate by High-Throughput Screening

Cited by 28 publications

References 21 publications

Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies

Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies

Potential Inhibitors for Isocitrate Lyase ofMycobacterium tuberculosisand Non-M. tuberculosis: A Summary

Advances in Mycobacterial Isocitrate Lyase Targeting and Inhibitors

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