title: New peptide deformylase inhibitors and cooperative interaction: a combination to improve antibacterial activity.
abstract: OBJECTIVE
  Bacterial drug resistance is a worrying public health problem and there is an urgent need for research and development to provide new antibacterial molecules. Peptide deformylase (PDF) is now a well-described intracellular target selected for the design of a new antibiotic group, PDF inhibitors (PDFIs). The initial bacterial susceptibility to an inhibitor of a cytoplasmic target is directly associated with the diffusion of the compound through the membrane barrier of Gram-negative bacteria and with its cytosolic accumulation at the required concentration.
  
  
  METHODS
  We have recently demonstrated that the activity of different PDFIs is strongly dependent on the accumulation of the active molecules by using permeabilizing agents, efflux inhibitors or efflux-mutated strains. In this work we assessed various combination protocols using different putative inhibitors (PDFIs, methionine aminopeptidase inhibitors etc.) to improve antibacterial activity against various resistant Gram-negative bacteria.
  
  
  RESULTS
  The maximum effect was observed when combining actinonin with a dual inhibitor of methionine aminopeptidase and PDF, this molecule being also able to interact with the target while actinonin is bound to the PDF active site.
  
  
  CONCLUSIONS
  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.
authors.affiliation: UMR-MD1, Transporteurs Membranaires,  Chimiorésistance et Drug-Design, Aix-Marseille Université, IRBA, Marseille,  France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Goemaere
authors.forename: Armelle
authors.initials: A
authors.lastname: Melet
authors.forename: Valéry
authors.initials: V
authors.lastname: Larue
authors.forename: Aurélie
authors.initials: A
authors.lastname: Lieutaud
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Alves de Sousa
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Chevalier
authors.forename: Liselotte
authors.initials: L
authors.lastname: Yimga-Djapa
authors.forename: Carmela
authors.initials: C
authors.lastname: Giglione
authors.forename: Florian
authors.initials: F
authors.lastname: Huguet
authors.forename: Mickael
authors.initials: M
authors.lastname: Alimi
authors.forename: Thierry
authors.initials: T
authors.lastname: Meinnel
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dardel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Artaud
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Pagès
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C084507:peptide deformylase