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Accueil > Equipes de recherche > Chimie Bio-inorganique des Dérivés Soufrés et Pharmacochimie > Thémes de recherche

Design, synthesis and biological evaluation of new antibacterial agents : new strategies of vectorization of a drug to its target.

publié le , mis à jour le

Isabelle Artaud, Rodolphe Alves de Sousa, Maryse Jaouen,Dominique Padovani, Erwan Galardon.

Post-docs and PhD students : Anas Allam (Post Doc 2010-2015) , Sandy Compain (PhD 2015), M. Alimi (PhD 2011), F. Huguet (PhD 2010), S. Petit (PhD 2007), A. Boularot (PhD 2005)
Collaborators :
J.-M. Pagès (UMR-MD1 IRBA Marseille), M. Réfrégiers (Synchrotron SOLEIL Gif-sur-Yvette), T. Meinnel (ISV Gif-sur-Yvette), N. Leulliot (UMR8015 Paris Descartes)

Antimicrobial résistance (AMR) is a major public health threat. Despite the need for new antimicrobials, very few effective molecules have been brought to the market these last decades. The urgency for novel drug candidates or for novel strategies to fight AMR is especially true when considering the increasing resistance of Gram negative bacteria to all known antibiotics. Our strategy for combatting this bacterial resistance was first to focus on targets, not yet explored with antibiotics available on the market and involved in biochemical processes that are essential to bacterial growth. In this regard, peptide deformylase (PDF) and methionine aminopeptidase (MetAP) are two metalloproteases of interest, since they are involved in the N-formyl methionine excision pathway (NME) that is essential to bacterial growth.In prokaryotes all nascent polypeptide chains are initiated with an N-formyl-methionine residue and NME requires the consecutive actions of PDF and MetAP to cleave the formyl group and the N-terminal methionine. So, we first developed new inhibitors targeting PDF and MetAP.
► Design, synthesis and in vitro activities of PDF and MetAP inhibitors.
We developed several series of hydroxamic acid inhibitors :
i) with an indole or an oxadiazole scaffold which are highly potent against E. coli PDF loaded with Ni(II) with IC50 in the nM range (J Med Chem 2007, ChemMedChem 2009, J Antimicrob Chemother 2012)
ii) with an oxazole or an oxadiazole scaffold which are selective for both the Mn(II) and Fe(II) forms versus the Co(II) form of E. coli MetAP with IC50 values around 1-2 microM (ChemMedChem 2012).

One of them (HA7) has been cristallized in complex with E. coli MetAP-Mn

► New strategies of vectorization of a drug to a metalloprotease target, without any modification of the drug structure.
While active in vitro, these compounds, as well as other compounds in the literature, only displayed poor antibacterial activities especially against Gram negative bacteria buttheir bacterial susceptibility can be improved by adding polymyxin nonapeptide (Plos One 2009). This relies on the severe restriction of penetration/diffusion rate through the outer membrane barrier (OM). Besides the low permeability of the OM which drastically reduces the intracellular concentration of active molecules, resistance results also from the overexpression of efflux systems that extrude the antibacterial agent from the cell before it can reach its target. To favor cell penetration, we developed chelating peptides possessing a short antimicrobial peptide analogue as permeabilizer or PA-beta-N (phenylalanine arginine-beta-naphthylamine) as efflux pump modulator grafted to a TPA or DPA ligand, that can be used in a 1:1 molar ratio or as drug carrier in Co(III) or Zn(II) metallodrugs with our hydroxamic acid inhibitors. All these systems are more efficient than any inhibitor tested alone (Bioconjugate Chemistry 2014 ). The mode of release of the drug fromCo(III) metallodrugs has been studied using model complexes (Inorg Chem 2012

► Development of assays to study penetration and efflux in multi-drug-resistant (MDR) Gram-negative pathogens.
These peptides with metal binding abilities proved to be active against E. aerogenes EA289, a MDR clinical isolate which has lost its sensitivity toward quinolones such as fleroxacin and ciprofloxacin. One of these peptides,AA23, labeled with a dansylated lysine has been imaged inside single cell resistant bacteria by deep ultraviolet fluorescence. The fluorescence intensity is clearly dependent on both the concentration of AA23 and the incubation time (ACS Med Chem Lett 2013

Recent publications
► New Peptides with Metal Binding Abilities and Their Use as Drug Carriers.
Allam, A. ; Maigre, L. ; Alimi, M. ; Alves de Sousa, R. ; Hessani, A. ; Galardon, E. ; Pages, J. M. ; Artaud, I.
Bioconjugate Chem., 2014, , in press, DOI: 10.1021/bc500317u
► New Peptide-based antimicrobials for tackling drug resistance in bacteria : single-cell fluorescence imaging.
Pages, J. M. ; Kascakova, S. ; Maigre, L. ; Allam, A. ; Alimi, M. ; Chevalier, J. ; Galardon, E. ; Refregiers, M. ; Artaud, I. Acs Med Chem Lett 2013, 4 (6), 556-9.
► New PDF-Inhibitors and Cooperative Interaction : a Combination to Improve Antibacterial Activity.
E. Goemaere, A. Melet, V. Larue, A. Lieutaud, R. Alves de Sousa, J.Chevalier, L.Yimga-DJjapa, C. Giglione, F. Huguet, M. Alimi, T. Meinnel, F.Dardel, I. Aartaud, J.-M. Pagès J. Antimicrob. Chemother, 2012, 67, 1392-1400
► Hydroxamic acids as potent inhibitors of Fe(II) and Mn(II) E. coli methionine aminopeptidase : biological activities and X-ray structures of oxazole hydroxamate-EcMetAP-Mn complexes.
Huguet, F. ; Melet, A. ; Alves de Sousa, R. ; Lieutaud, A. ; Chevalier, J. ; Maigre, L. ; Deschamps, P. ; Tomas, A. ; Leulliot, N. ; Pages, J. M. ; Artaud, I. ChemMedChem 2012, 7 (6), 1020-30
► Characterization of cobalt(III) hydroxamic acid complexes based on a tris(2-pyridylmethyl)amine scaffold : reactivity toward cysteine methyl ester
Alimi, M. ; Allam, A. ; Selkti, M. ; Tomas, A. ; Roussel, P. ; Galardon, E. ; Artaud, I Inorg. Chem. 2012, 17, 9350-6.