New peptide deformylase inhibitors and cooperative interaction: a combination to improve antibacterial activity

Goemaere, Emilie L.; Melet, Armelle; Larue, Valéry; Lieutaud, Aurélie; Sousa, Rodolphe Alves de; Chevalier, Jacqueline; Yimga-Djapa, Liselotte; Giglione, Carmela; Huguet, Florian; Alimi, Mickael; Meinnel, Thierry; Dardel, Frédéric; Artaud, Isabelle; Pagès, Jean‐Marie

doi:10.1093/jac/dks058

Cited by 19 publications

(16 citation statements)

References 44 publications

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“…2 Inhibition of the bacterial PDF causes stasis of bacterial cells, 3 and PDF is currently an emerging target for antibiotic research. 4, 5 Our lab has characterized the functions of human mitochondrial protein peptide deformylase (HsPDF). 6, 7, 8, 9 Mammalian PDFs are capable of removing the formyl group of N-terminally formylated peptides, which are derived from the proteins encoded by the mitochondrial DNA.…”

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confidence: 99%

Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers

et al. 2014

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Inhibition of human mitochondrial peptide deformylase (HsPDF) depolarizes the mitochondrial membrane, reduces mitochondrial protein translation and causes apoptosis in Burkitt's lymphoma. We showed that HsPDF mRNA and protein levels were overexpressed in cancer cells and primary acute myeloid leukemia samples. Myc regulates mitochondria and metabolism; we also demonstrated c-myc regulated the expression of HsPDF, likely indirectly. Inhibition of HsPDF by actinonin blocked mitochondrial protein translation and caused apoptotic death of myc-positive Burkitt's lymphoma, but not myc-negative B cells. Inhibition of mitochondrial translation by chloramphenicol or tetracycline, structurally different inhibitors of the mitochondrial ribosome, which is upstream of deformylase activity, followed by treatment with actinonin, resulted in reversal of the biochemical events and abrogation of the apoptosis induced by actinonin. This reversal was specific to inhibitors of HsPDF. Inhibition of HsPDF resulted in a mitochondrial unfolded protein response (increased transcription factors CHOP and CEB/P and the mitochondrial protease Lon), which may be a mechanism mediating cell death. Therefore, HsPDF may be a therapeutic target for these hematopoietic cancers, acting via a new mechanism.

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confidence: 99%

Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers

et al. 2014

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“…1b–d ) containing an oxazole ( Fig. 1d ) or an oxadiazole 38 ( Fig. 1b,c ) as isostere of amide functions.…”

Section: Resultsmentioning

confidence: 99%

“…1a ), the first potent PDF inhibitor characterized, showing a dissociation constant in the low nanomolar range 31 . Actinonin cannot be used in therapeutics for several reasons: (i) it targets also several metalloenzymes in addition to PDFs 32 33 , (ii) it induces apoptosis and other cytotoxic effects 21 24 28 34 35 , (iii) it is rapidly exported by bacterial efflux pumps and therefore exhibits moderate in vivo activity 36 37 38 and (iv) it induces resistance with a relatively high frequency through various mechanisms most often leading to a by-pass of the formylation pathway 39 40 41 42 43 . Nevertheless, actinonin remains the reference compound for the rational design of new anti-PDF compounds because of its high potency attained through a two-step, time-dependent inhibition mechanism called slow tight-binding.…”

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confidence: 99%

“…Interestingly, most of the potent anti-PDF molecules exhibit slow tight-binding behavior 28 44 50 51 . In addition many PDF inhibitors induce moderate cytotoxic effects 48 and display antimicrobial activity, particularly when used together with membrane permeabilizers 37 38 . Moreover, synergistic effects have been observed when two drugs were applied at the same time 38 52 .…”

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A unique peptide deformylase platform to rationally design and challenge novel active compounds

Fieulaine

Sousa

Maigre

et al. 2016

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Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.

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“…7 Very recently, a diketo acid coupled with L-alanine methyl ester has been reported as EcMetAP inhibitor. 8 Considering the large pharmacological importance of b-diketo acids and in continuation to our efforts to explore novel biologically active molecules, 9,10 in-house database of 201 compounds virtual library was screened against Escherichia coli MetAP (EcMetAP). Based on this preliminary data, diketoesters (1a-m), diketo acids (2a-f, 2h, 2m) were selected and synthesized in good yields.…”

Section: Introductionmentioning

confidence: 99%

Diketo acids and their amino acid/dipeptidic analogues as promising scaffolds for the development of bacterial methionine aminopeptidase inhibitors

et al. 2015

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Using diketoesters as the template, various derivatives were designed and the selected compounds were synthesized as bacterial methionine aminopeptidase (MetAP) inhibitors. The results of in vitro antibacterial screening revealed fifteen compounds (1a-c, 1e-h, 1j, 1l, 2a-c, 3d, 5c and 5e) as potent against different bacterial strains. By using the MTT assay on human cell line (HepG2), the viability of cell proliferation was evaluated and nine compounds (1c, 1e, 1j, 1l, 2a,b, 3d, 5c and 5e) showed no cytotoxic effect at the concentration range of 50-450 mg ml À1 . In the biochemical evaluation against methionine aminopeptidase (MetAPs) from Streptococcus pneumonia (SpMetAP), Mycobacterium tuberculosis (MtMetAP), Enterococcus faecalis (EfMetAP) and human (HsMetAP), compounds displayed differential behaviour against these four enzymes. Moreover, compound 1g showed 84% inhibition of SpMetAP, while compound 3d selectively inhibited MtMetAP with 79% inhibition and little effect on HsMetAP at 100 mM concentration. At the same concentration, compound 5e exhibited 87% and 85% inhibition of EfMetAP and SpMetAP, respectively. Understanding the mode of binding through modeling at the active site provided the structural basis for the possible mode of inhibition. Together, these data will be useful for further development of diketo acid based inhibitors with improved potency and selectivity.

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New peptide deformylase inhibitors and cooperative interaction: a combination to improve antibacterial activity

Abstract: Such a combination of inhibitors acting on two tightly associated metabolic steps results in a cooperative effect on bacterial cells and opens an original way to combat multidrug-resistant bacteria.

Cited by 19 publications

References 44 publications

Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers

Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers

A unique peptide deformylase platform to rationally design and challenge novel active compounds

Diketo acids and their amino acid/dipeptidic analogues as promising scaffolds for the development of bacterial methionine aminopeptidase inhibitors

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