Growth inhibition of Mycobacterium smegmatis by prodrugs of deoxyxylulose phosphate reducto-isomerase inhibitors, promising anti-mycobacterial agents

Ponaire, Sarah; Zinglé, Catherine; Tritsch, Denis; Grosdemange-Billiard, Catherine; Rohmer, Michel

doi:10.1016/j.ejmech.2012.02.031

Cited by 22 publications

(25 citation statements)

References 51 publications

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“…It is possible that these bacteria were not able to metabolize the prodrug or that the pro-drug is not effective at crossing the double membrane, because they are too lipophilic to transverse the hydrophilic transmembrane space. However, another group recently has reported activity of the bis-POM derivative 94 in mycobacterium [222]. All in all, future studies that focus on prodrugs of more metabolically stable compounds such as these would be well worthwhile.…”

Section: Current Applications Of Prodrug Technologymentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

148

135

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A substantial portion of metabolism involves transformation of phosphate esters, including pathways leading to nucleotides and oligonucleotides, carbohydrates, isoprenoids and steroids, and phosphorylated proteins. Because the natural substrates bear one or more negative charges, drugs that target these enzymes generally must be charged as well but small charged molecules can have difficulty traversing the cell membrane other than by endocytosis. The resulting dichotomy has stimulated abundant effort to develop effective prodrugs, compounds that carry little or no charge to enable them to transit biological membranes but then able to release the parent drug once inside the target cell. This chapter will present recent studies on advances in prodrug forms, along with representative examples of their application to marketed and developmental drugs.

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Section: Current Applications Of Prodrug Technologymentioning

confidence: 99%

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer

2014

Topics in Current Chemistry

148

135

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“…Several double ester prodrugs based on the original structures of LK1 (derived from fosmidomycin) and LK2 (derived from FR-900098) were recently synthesized 79 . They will be referred to as SP1 to SP6 in this work ( Figure S4).…”

Section: Resultsmentioning

confidence: 99%

“…It was also important to see whether the bioassay may prove to be valuable for a statistical approach. As all inhibitors, with the exception of LK1, were found to be totally inhibitory at 100µM we started testing six prodrug derivatives of LK1 at 50µM 79 to detect a first “all-or-nothing” effect. At 50µM, all the six prodrugs were able to induce a mislocalization of the H 6 -GFP-BD-CVIL fusion protein in at least 50% of treated cells.…”

Section: Resultsmentioning

confidence: 99%

“…II) Three molecules with a methyl group bound to the N-atom (derived from LK2: SP2, SP4 and SP6). The respective phosphonate groups were masked as acyloxymethyl phosphonate esters 79 . Cells were pre-treated for 3 h with 50µM of each inhibitor (solvent: methanol) before expression of H 6 -GFP-DB-CVIL was induced by addition of dexamethasone (10µM final concentration).…”

Section: Resultsmentioning

confidence: 99%

“…The test of the six new prodrugs 79 , here referred to as SP1 to SP6, includes a whole new aspect: for the first time, novel drugs specifically designed on the basis of known pathway inhibitors were tested under standardized conditions and the generated data were exploited in both a qualitative and a quantitative/statistical way. This means that, besides answering the question of whether an inhibitor candidate could efficiently block the MEP pathway, the exploitation of the same set of data would allow a direct comparison of the efficiency of this compound with established MEP pathway inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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The effect of MEP pathway and other inhibitors on the intracellular localization of a plasma membrane-targeted, isoprenylable GFP reporter protein in tobacco BY-2 cells

et al. 2013

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We have established an in vivo visualization system for the geranylgeranylation of proteins in a stably transformed tobacco BY-2 cell line, based on the expression of a dexamethasone-inducible GFP fused to the carboxy-terminal basic domain of the rice calmodulin CaM61, which naturally bears a CaaL geranylgeranylation motif (GFP-BD-CVIL). By using pathway-specific inhibitors it was demonstrated that inhibition of the methylerythritol phosphate (MEP) pathway with known inhibitors like oxoclomazone and fosmidomycin, as well as inhibition of the protein geranylgeranyltransferase type 1 (PGGT-1), shifted the localization of the GFP-BD-CVIL protein from the membrane to the nucleus. In contrast, the inhibition of the mevalonate (MVA) pathway with mevinolin did not affect the localization. During the present work, this test system has been used to examine the effect of newly designed inhibitors of the MEP pathway and inhibitors of sterol biosynthesis such as squalestatin, terbinafine and Ro48-8071. In addition, we also studied the impact of different post-prenylation inhibitors or those suspected to affect the transport of proteins to the plasma membrane on the localization of the geranylgeranylable fusion protein GFP-BD-CVIL.

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