Phosphonate inhibitors of antigen 85C, a crucial enzyme involved in the biosynthesis of the Mycobacterium tuberculosis cell wall

Gobec, Stanislav; Plantan, Ivan; Mravljak, Janez; Wilson, Rosalind A.; Besra, Gurdyal S.; Kikelj, D.

doi:10.1016/j.bmcl.2004.04.052

Cited by 35 publications

(21 citation statements)

References 18 publications

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“…110 Kovac et al prepared sulfonate ( 74 ) inhibitors similar to Gobec et al and obtained an IC 50 = 4.3 μM. 111 The assays used for evaluating inhibition of above trehalose and AG analogs and transition state analogs are discussed below.…”

Section: Trehalose Utilization Pathways (Tups)mentioning

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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Section: Trehalose Utilization Pathways (Tups)mentioning

confidence: 99%

Targeting the trehalose utilization pathways ofMycobacterium tuberculosis

Thanna

Sucheck

2016

Med. Chem. Commun.

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“…First, Belisle et al showed that 6-azido-6-deoxy-α,α′-trehalose, an analog of trehalose, inhibited the activity of Ag85C by 60% at a concentration of 100 μg/ml [84]. Then, different libraries of compounds based on trehalose analogs [93,94] or mimics of the tetrahedral transition state [95–97] were screened using the assay developed by Belisle.…”

Section: The Antigen 85 Complexmentioning

confidence: 99%

Targeting the mycobacterial envelope for tuberculosis drug development

Favrot

Ronning²

2012

Expert Review of Anti-infective Therapy

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The bacterium that causes tuberculosis, Mycobacterium tuberculosis, possesses a rather unique outer membrane composed largely of lipids that possess long-chain and branched fatty acids, called mycolic acids. These lipids form a permeability barrier that prevents entry of many environmental solutes, thereby making these bacteria acid-fast and able to survive extremely hostile surroundings. Antitubercular drugs must penetrate this layer to reach their target. This review highlights drug development efforts that have added to the slowly growing tuberculosis drug pipeline, identified new enzyme activities to target with drugs and increased the understanding of important biosynthetic pathways for mycobacterial outer membrane and cell wall core assembly. In addition, a portion of this review looks at discovery efforts aimed at weakening this barrier to decrease mycobacterial virulence, decrease fitness in the host or enhance the efficacy of the current drug repertoire by disrupting the permeability barrier.

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“…Isoniazid and ethionamide inhibit biosynthesis of mycolic acids . Obviously, the crystal structure of antigen 85 complex is expected to accelerate the design of new drugs against Ag85 activity and cord factor biosynthesis (Table 1) (Gobec et al, 2004;Sanki et al, 2009b;Wang et al, 2004).…”

Section: Ag85 As a Putative Drug Target For Tuberculosis Treatmentmentioning

confidence: 99%

“…Methyl -D-arabinofuranoside (Sanki et al, 2009b) Ag85C 5-S-alkyl-5-thioarabinofuranoside analogues (Sanki et al, 2008) Ag85 complex Trehalose analogues (Wang et al, 2004) Ag85 complex ADT (6-azido-6-deoxy-, ′-trehalose) (Belisle et al, 1997;Mizuguchi et al, 1983) Ag85 complex Phosphonate compounds (Gobec et al, 2004;Gobec et al, 2007) Ag85C DEP (Diethyl phosphate) (Ronning et al, 2000) The mycobacterial glycolipids and TMM levels in the cell wall might give an indirect indication of the fitness of the cell inside the host cells specially in macrophages. Thus the quantitation of the mycobacterial TMM status after drug treatment may allow the estimation of drug effectiveness.…”

Section: Ag85cmentioning

confidence: 99%