Efflux pumps of gram-negative bacteria, a new target for new molecules
| Autor: | Jean-Marie Pagès, Sandrine Alibert-Franco, Abdallah Mahamoud, Jean-Michel Bolla, Jacqueline Chevalier, Eric Garnotel, Anne Davin-Regli |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Gram-negative bacteria
biology medicine.drug_class Drug discovery Antibiotics Transporter Drug resistance General Medicine biology.organism_classification Ion Channels Microbiology Anti-Bacterial Agents Antibiotic resistance Biochemistry Drug Resistance Multiple Bacterial Drug Discovery Gram-Negative Bacteria medicine Humans Efflux Bacteria |
| Zdroj: | Current topics in medicinal chemistry. 10(18) |
| ISSN: | 1873-4294 |
| Popis: | Antibiotic resistance mechanisms reported in Gram-negative bacteria are a worldwide health problem. The continuous dissemination of multi-drug resistant (MDR) bacteria drastically reduces the efficacy of our antibiotic “arsenal” and consequently increases the frequency of therapeutic failure. In MDR bacteria the over-expression of efflux pumps expel structurally-unrelated antibiotics decreasing their intracellular concentration. It is necessary to clearly define the molecular and genetic bases of the efflux pump in order to combat this mechanism. The characterization of efflux pumps, from genetic to structural studies, allows the definition of a new, original antiresistance bullet, the efflux pump inhibitor (EPI). This new class of antibacterial molecules may act conjointly to the usual antibiotic in order to restore its activity. Several families of EPIs have been now reported and described. The use of these EPIs promotes a significant increase of susceptibility to one or more antibiotics in strains or clinical isolates which were initially resistant. These EPIs may target different efflux targets, (i) the expression of genes that induces MDR, the transporters that pump the antibiotic out of bacterium, (ii) the assembly of membrane transporter complex involved in drug efflux, (iii) the energy involved in this active transport, (iv) the inhibition of the flux of molecules inside the efflux channel by competition or blocking (via steric hindrances). With the recent thorough characterization of the efflux pump AcrB at its structural and physiological level including the identification of drug affinity sites and kinetic parameters for some antibiotics, it is now possible to rationally develop an improved new generation of EPIs. |
| Databáze: | OpenAIRE |
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