Discovery and Refinement of a New Structural Class of Potent Peptide Deformylase Inhibitors

Boularot, Adrien; Giglione, Carmela; Petit, Sylvain; Duroc, Yann; Sousa, Rodolphe Alves de; Larue, Valéry; Cresteil, Thierry; Dardel, Frédéric; Artaud, Isabelle; Meinnel, Thierry

doi:10.1021/jm060910c

Cited by 61 publications

(96 citation statements)

References 38 publications

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“…Possibly, the mammalian PDF, which appears to be an essential enzyme, is protected from these drugs by the low permeability of the mitochondrial membranes [143]. In addition, several inhibitors of bacterial PDF are less active against the mammalian enzyme, presumably due to structural differences of the enzymes [138,144]. Recombinant PDF of P. falciparum is inhibited by actinonin 58 with an IC 50 of 2.5 M, which is much higher than the K i of 0.3 nM for E. coli PDF [145].…”

Section: Peptide Deformylasementioning

confidence: 99%

“…In the P. vinckei mouse model actinonin 58 is inactive, which may reflect an unfavourable pharmacokinetic behaviour since it has also no activity against bacteria in mice. Structurally very simple indole-based PDF inhibitors have been developed [144]. Compound 59 inhibits PDF of E. coli with an IC 50 of 0.035 M compared to 0.01 M for actinonin (Fig.…”

Section: Peptide Deformylasementioning

confidence: 99%

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The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

Wiesner

Reichenberg²,

Heinrich³

et al. 2008

CPD

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Apicomplexan parasites infectious to humans include Plasmodium spp., Babesia spp., Toxoplasma gondii, Cryptosporidium spp., Isospora belli and Cyclospora cayetanensis. With exception of Cryptosporidium spp., these parasites possess a non-photosynthetic plastid-like organelle called apicoplast. The apicoplast possesses a small circular genome and harbours prokaryotic-type biochemical pathways. As the most important metabolic functions, the mevalonate independent 1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid synthesis and the type II fatty acid synthesis system are operative inside the apicoplast. Classical antibacterial drugs such as ciprofloxacin, tetracycline, doxycycline, clindamycin and spiramycin inhibit the apicoplast-located gyrase and translation machinery, respectively, and are currently used in the clinic for the treatment of infections with apicomplexan parasites. As an inhibitor of isoprenoid synthesis, fosmidomycin was proven to be effective against acute P. falciparum malaria in clinical phase II studies. Triclosan, an inhibitor of fatty acid synthesis, was active in a malaria mouse model. In vitro antimalarial activity was shown for inhibitors of peptide deformylase and the import of apicoplast-targeted proteins. Work on various other inhibitors of apicoplast-located biochemical processes is ongoing.

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Section: Peptide Deformylasementioning

confidence: 99%

Section: Peptide Deformylasementioning

confidence: 99%

The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

Wiesner

Reichenberg²,

Heinrich³

et al. 2008

CPD

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“…Resistant strains grew at concentrations much higher than four times the MIC (Table 1). Actinonin-resistant mutants did not show any cross-resistance to other antibiotics but were resistant to other classes of PDFI (7). Both open reading frame and promoter regions of genes (def, ykrB, fmt, and folD), the alteration or loss of function of which causes actinonin resistance in other bacteria, were sequenced.…”

mentioning

confidence: 99%

Mutations in Three Distinct Loci Cause Resistance to Peptide Deformylase Inhibitors inBacillus subtilis

Duroc

Giglione

Meinnel

2009

Antimicrob Agents Chemother

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Bacillus subtilis mutants with resistance against peptide deformylase inhibitors were isolated. All showed a bypass of the pathway through mutations in three genes required for formylation of Met-tRNA fMet , fmt, folD, and glyA. glyA corresponds to a yet uncharacterized locus inducing resistance. The bypass of formylation caused robust fitness reduction but was not accompanied by alterations of the transcription profile. A subtle adaptation of the enzymes of the intermediary metabolism was observed.In bacteria, all newly synthesized polypeptides transiently carry a formylated N terminus (1,18,33). Peptide deformylase (PDF) catalyzes the subsequent removal of the formyl group, and its gene is essential (11,22,23). The natural compound actinonin was the first PDF inhibitor (PDFI) characterized (4, 6, 8). Mechanisms causing PDFI resistance involve (i) mutations in the target gene, (ii) bypassing of the formylation pathway, or (iii) efflux of PDFI (4,9,10,15,17,19,20,25,31). Bacillus subtilis has two functional PDF genes, def and ykrB (14). The mechanisms of resistance have been studied only in bacteria expressing one active PDF gene. No analysis has approached the implications beyond the fitness cost often associated with PDFI resistance.To isolate variants resistant to PDFI, 100 l of an exponential-phase B. subtilis culture was plated onto Mueller-Hinton (MH) agar supplemented with 12 g/ml of actinonin. The plates were incubated for 2 days at 37°C, after which resistant colonies were restreaked and isolated. Cells were also plated

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“…1 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 drops of concentrated sulfuric acid were added. The mixture was heated under reflux for 2 h, cooled to rt, neutralized with a solution of NaOH 2M, and evaporated to dryness in vacuo.…”

Section: -(2-(5-methoxy-1h-indol-3-yl)ethyl)-5-methyloxazole (8)mentioning

confidence: 99%

Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential

et al. 2015

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Herein we present a new family of melatonin-based compounds, in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4-oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compounds were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. We also found that several of these melatonin-based compounds promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacological studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures.

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Discovery and Refinement of a New Structural Class of Potent Peptide Deformylase Inhibitors

Cited by 61 publications

References 38 publications

The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

Mutations in Three Distinct Loci Cause Resistance to Peptide Deformylase Inhibitors inBacillus subtilis

Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential

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