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Article Dans Une Revue Journal of Antimicrobial Chemotherapy Année : 2012

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

Résumé

OBJECTIVES: 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.
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Dates et versions

hal-00851369 , version 1 (13-08-2013)

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Emilie Goemaere, Armelle Melet, Valéry Larue, Aurélie Lieutaud, Rodolphe Alves de Sousa, et al.. New peptide deformylase inhibitors and cooperative interaction: a combination to improve antibacterial activity.. Journal of Antimicrobial Chemotherapy, 2012, 67 (6), pp.1392-400. ⟨10.1093/jac/dks058⟩. ⟨hal-00851369⟩
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