New tuberculosis drug development: targeting the shikimate pathway

Kapnick, Senta M.; Zhang, Ying

doi:10.1517/17460441.3.5.565

Cited by 15 publications

(8 citation statements)

References 114 publications

(140 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Chorismic acid, which is synthesized through the shikimic acid pathway, is the precursor of aromatic amino acids and other metabolites, including folates, ubiquinones, mycobactins, menaquinones, and napthoquinones 3 . Genomic studies have shown that this biosynthetic route is essential in bacteria, fungi, algae, higher plants, and some parasites, such as the human malaria-causing parasite Plasmodium falciparum 4 – 6 .…”

Section: Introductionmentioning

confidence: 99%

IMB-T130 targets 3-dehydroquinate synthase and inhibits Mycobacterium tuberculosis

Zhu

Wang

et al. 2018

Sci Rep

View full text Add to dashboard Cite

The anti-tuberculosis (TB) agent IMB-T130 was speculated to be a multi-target compound. In this research, we found that IMB-T130 inhibits the catalytic activity of Mycobacterium tuberculosis 3-dehydroquinate synthase (MtDHQS), the enzyme in the second step of the shikimate pathway. IMB-T130 was identified as a selective inhibitor of MtDHQS with an IC50 value of 0.87 μg/mL. The interaction between the compound and protein was analysed by surface plasmon resonance and circular dichroism. Based on the in silico molecular docking results, the essential amino acids in the binding pocket were then confirmed by site-directed mutagenesis. Overexpression of DHQS reduced the antibacterial activity of IMB-T130 in cells, verifying that DHQS is the target of IMB-T130. IMB-T130 inhibited standard and drug-resistant M. tuberculosis strains by targeting DHQS. Our findings improve our understanding of MtDHQS and make it to be a potential target for new anti-TB drug discovery.

show abstract

Section: Introductionmentioning

confidence: 99%

IMB-T130 targets 3-dehydroquinate synthase and inhibits Mycobacterium tuberculosis

Zhu

Wang

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This enzyme is considered an excellent target for developing novel anti-tuberculosis agents as the pathway in which it is involved only takes place in microbes and some plants but is absent in mammals [ 11 ]. The shikimate pathway involves seven enzymatic steps in the biosynthesis of chorismate end product, which in turn serves as the precursor for the synthesis of the aromatic amino acids, folates, uniquinones, mycobactins, menaquinones and napthoquinones [ 12 ]. The importance of this pathway has been proven in culture using mutants whose growth is completely inhibited without the provision of aromatic supplements [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Isolation of alpha-linolenic acid from Sutherlandia frutescens and its inhibition of Mycobacterium tuberculosis’ shikimate kinase enzyme

Masoko

Mabusa

Howard

2016

BMC Complement Altern Med

View full text Add to dashboard Cite

BackgroundSutherlandia frutescens (L) R.Br. is one of traditional herbal medicines that formed the basis of primary health care systems since the earliest days and is still widely used. Sutherlandia is prescribed for people with tuberculosis (TB), but is still not known which compound(s) acts against M. tuberculosis and its mode of action. The aim of this study was to identify and isolate antimycobacterial compounds from S. frutescens extracts against shikimate kinase, a drug target for M. tuberculosis.MethodsS. frutescens were dried, ground and extracted with ethanol, dichloromethane: methanol and water. Fractionation and separation of compounds was done with column chromatography. Chromatograms were developed in butanol/acetic acid/water (BAW) [21:6:3]; chloroform/methanol/water/formic acid (CMWF1) [60:15:2:1] and (CMWF2) [21:9:1:0.3]. Separation and isolation of active compounds were done using preparative HPLC. The activity of the plant extracts were also screened against shikimate kinase enzyme (MtbSK) using the MtbSK inhibition assay.ResultsThe DCM: MeOH (1:1) extract showed a high percentage inhibition (with an IC50 of 0.1 μg/ml) of MtbSK and the purified inhibitor was an Alpha-Linolenic Acid (ALA) compound and it had a significant IC50 of 3.7 μg/ml.ConclusionsThis study demonstrated that ALA from S. frustescens is an inhibitor of shikimate kinase a good drug target for M. tuberculosis.

show abstract

“…This route, that combines glucose and pentose phosphate metabolism, involves seven reactions that convert erytrose-4-phosphate and phosphoenolpyruvate to chorismate, which is the precursor for the synthesis of important metabolites such as aromatic amino acids, ubiquinone and folate [8]. The shikimate pathway is present in plants, fungi, apicomplexan parasites and bacteria, but is absent in humans, a characteristic that makes its enzymes excellent targets for drug discovery [8,9,10].…”

Section: Introductionmentioning

confidence: 99%

Inhibition and Biochemical Characterization of Methicillin-Resistant Staphylococcus aureus Shikimate Dehydrogenase: An in Silico and Kinetic Study

et al. 2014

View full text Add to dashboard Cite

Methicillin-resistant Staphylococcus auerus (MRSA) strains are having a major impact worldwide, and due to their resistance to all β-lactams, an urgent need for new drugs is emerging. In this regard, the shikimate pathway is considered to be one of the metabolic features of bacteria and is absent in humans. Therefore enzymes involved in this route, such as shikimate dehydrogenase (SDH), are considered excellent targets for discovery of novel antibacterial drugs. In this study, the SDH from MRSA (SaSDH) was characterized. The results showed that the enzyme is a monomer with a molecular weight of 29 kDa, an optimum temperature of 65 °C, and a maximal pH range of 9-11 for its activity. Kinetic studies revealed that SDH showed Michaelis-Menten kinetics toward both substrates (shikimate and NADP + ). Initial velocity analysis suggested that SaSDH catalysis followed a sequential random mechanism. Additionally, a tridimensional model of SaSDH was obtained by homology modeling and validated. Through virtual screening three OPEN ACCESSMolecules 2014, 19 4492 inhibitors of SaSDH were found (compounds 238, 766 and 894) and their inhibition constants and mechanism were obtained. Flexible docking studies revealed that these molecules make interactions with catalytic residues. The data of this study could serve as starting point in the search of new chemotherapeutic agents against MRSA.

show abstract

New tuberculosis drug development: targeting the shikimate pathway

Abstract: Shikimate pathway enzymes, especially shikimate kinase, may offer attractive targets for new TB drug and vaccine development.

Cited by 15 publications

References 114 publications

IMB-T130 targets 3-dehydroquinate synthase and inhibits Mycobacterium tuberculosis

IMB-T130 targets 3-dehydroquinate synthase and inhibits Mycobacterium tuberculosis

Isolation of alpha-linolenic acid from Sutherlandia frutescens and its inhibition of Mycobacterium tuberculosis’ shikimate kinase enzyme

Inhibition and Biochemical Characterization of Methicillin-Resistant Staphylococcus aureus Shikimate Dehydrogenase: An in Silico and Kinetic Study

Contact Info

Product

Resources

About