Antitubercular Drugs Based on Carbohydrate Derivatives

Gaitonde, Vishwanath; Sucheck, Steven J.

doi:10.1142/9781783267200_0018

Cited by 5 publications

(4 citation statements)

References 187 publications

(287 reference statements)

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“…1 In order to eradicate TB there is a need to identify new compounds and drug targets which act faster and show activity in drug resistant Mtb strains. 2,3 …”

Section: Introductionmentioning

confidence: 99%

Zwitterionic pyrrolidene-phosphonates: inhibitors of the glycoside hydrolase-like phosphorylase Streptomyces coelicolor GlgEI-V279S

et al. 2017

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We synthesized and evaluated new zwitterionic inhibitors against glycoside hydrolase-like phosphorylase Streptomyces coeticotor (Sco) GlgEI-V279S which plays a role in α-glucan biosynthesis. Sco GlgEI-V279S serves as a model enzyme for validated anti-tuberculosis (TB) target Mycobacterium tuberculosis (Mtb) GlgE. Pyrrolidine inhibitors 5 and 6 were designed based on transition state considerations and incorporate a phosphonate on the pyrrolidine moiety to expand the interaction network between the inhibitor and the enzyme active site. Compounds 5 and 6 inhibited Sco GlgEI-V279S with Ki = 45 ± 4 μM and 95 ± 16 μM, respectively, and crystal structures of Sco GlgE-V279S-5 and Sco GlgE-V279S-6 were obtained at a 3.2 Å and 2.5 Å resolution, respectively.

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“…1 In order to eradicate TB there is a need to identify new compounds and drug targets which act faster and show activity in drug resistant Mtb strains. 2,3 …”

Section: Introductionmentioning

confidence: 99%

Zwitterionic pyrrolidene-phosphonates: inhibitors of the glycoside hydrolase-like phosphorylase Streptomyces coelicolor GlgEI-V279S

et al. 2017

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“…In recent years there have been sustained efforts to make a breakthrough in anti-tuberculosis drug development utilizing this key strategic information. Sucheck and co-workers developed a series of considerably effective trehalose and other glyco-conjugate-based Mtb GlgE inhibitors [217,218,219,220]. Another important chemical moiety from the classical medicinal chemistry viewpoint are the pyrazolo[1,5-a]pyrimidine and its derivatives.…”

Section: Small Particles As Antibioticsmentioning

confidence: 99%

Promising Recent Strategies with Potential Clinical Translational Value to Combat Antibacterial Resistant Surge

Karmakar

Gaitonde²

2019

Medicines

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Multiple drug resistance (MDR) for the treatment of bacterial infection has been a significant challenge since the beginning of the 21st century. Many of the small molecule-based antibiotic treatments have failed on numerous occasions due to a surge in MDR, which has claimed millions of lives worldwide. Small particles (SPs) consisting of metal, polymer or carbon nanoparticles (NPs) of different sizes, shapes and forms have shown considerable antibacterial effect over the past two decades. Unlike the classical small-molecule antibiotics, the small particles are less exposed so far to the bacteria to trigger a resistance mechanism, and hence have higher chances of fighting the challenge of the MDR process. Until recently, there has been limited progress of clinical treatments using NPs, despite ample reports of in vitro antibacterial efficacy. In this review, we discuss some recent and unconventional strategies that have explored the antibacterial efficacy of these small particles, alone and in combination with classical small molecules in vivo, and demonstrate possibilities that are favorable for clinical translations in near future.

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“…Some of the most effective approaches for targeting Mtb , and bacteria in general, have been to target the bacterial cell wall. 8–10 For example, the first line TB antibiotics H/Inh, E/Emb target enzymes required for biosynthesis of cell wall building blocks and assembly of the cell wall or hydrophobic layer. We have chosen to focus on the trehalose utilization pathways (TUPs) since they contain several genetically validated targets and also play essential roles in cell wall and glycolipid synthesis.…”

Section: Introductionmentioning

confidence: 99%

“…Trehalose monomycolate (TMM), trehalose dimycolate (TDM, Cord Factor), phenolic glycolipids (PGL), phosphatidylinositol mannosides (PIMs), phosphatidylethanolamine (PE), triacylglycerols (TAGs), phospholipids, and lipoarabinomannan (LAM) are all non-covalently associated with the lipid layer. 8–10 Among all the lipids TDM (Cord Factor) is the most abundant lipid released by virulent Mtb . 6 In host macrophage cells C-type lectin Mincle receptor recognizes TDM.…”

Section: Introductionmentioning

confidence: 99%

Targeting the trehalose utilization pathways ofMycobacterium tuberculosis

Thanna

Sucheck

2016

Med. Chem. Commun.

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Tuberculosis (TB) is an epidemic disease and the growing burden of multidrug-resistant (MDR) TB world wide underlines the need to discover new drugs to treat the disease. Mycobacterium tuberculosis (Mtb) is the etiological agent of most cases of TB. Mtb is difficult to treat, in part, due to the presence of a sturdy hydrophobic barrier that prevents penetration of drugs through the cell wall. Mtb can also survive in a non-replicative state for long periods of time avoiding the action of common antibiotics. Trehalose is an essential metabolite in mycobacteria since it plays key roles in cell wall synthesis, transport of cell wall glycolipids, and energy storage. It is also known for its stress protective roles such as: protection from desiccation, freezing, starvation and osmotic stress in bacteria. In this review we discuss the drug discovery efforts against enzymes involved in the trehalose utilization pathways (TUPs) and their likelihood of becoming drug targets.

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Antitubercular Drugs Based on Carbohydrate Derivatives

Cited by 5 publications

References 187 publications

Zwitterionic pyrrolidene-phosphonates: inhibitors of the glycoside hydrolase-like phosphorylase Streptomyces coelicolor GlgEI-V279S

Zwitterionic pyrrolidene-phosphonates: inhibitors of the glycoside hydrolase-like phosphorylase Streptomyces coelicolor GlgEI-V279S

Promising Recent Strategies with Potential Clinical Translational Value to Combat Antibacterial Resistant Surge

Targeting the trehalose utilization pathways ofMycobacterium tuberculosis

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