New Antibiotic Molecules: Bypassing the Membrane Barrier of Gram Negative Bacteria Increases the Activity of Peptide Deformylase InhibitorsReport as inadecuate




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Background

Multi-drug resistant MDR bacteria have become a major concern in hospitals worldwide and urgently require the development of new antibacterial molecules. Peptide deformylase is an intracellular target now well-recognized for the design of new antibiotics. The bacterial susceptibility to such a cytoplasmic target primarily depends on the capacity of the compound to reach and accumulate in the cytosol.

Methodology-Principal Findings

To determine the respective involvement of penetration influx and pumping out efflux mechanisms to peptide deformylase inhibitors PDF-I activity, the potency of various series was determined using various genetic contexts efflux overproducers or efflux-deleted strains and membrane permeabilizers. Depending on the structure of the tested molecules, two behaviors could be observed: i for actinonin the first PDF-I characterized, the AcrAB efflux system was the main parameter involved in the bacterial susceptibility, and ii, for the lastest PDF-Is such as the derivatives of 2-5-bromo-1H-indol-3-yl-N-hydroxyacetamide, the penetration through the membrane was a important limiting step.

Conclusions-Significance

Our results clearly show that the bacterial membrane plays a key role in modulating the antibacterial activity of PDF-Is. The bacterial susceptibility for these new antibacterial molecules can be improved by two unrelated ways in MDR strains: by collapsing the Acr efflux activity or by increasing the uptake rate through the bacterial membrane. The efficiency of the second method is associated with the nature of the compound.



Author: Laurent Mamelli, Sylvain Petit, Jacqueline Chevalier, Carmela Giglione, Aurélie Lieutaud, Thierry Meinnel, Isabelle Artaud, Jean

Source: http://plos.srce.hr/



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