Efflux Pumps of Gram-Negative Bacteria, a New Target for New Molecules

Jean-Marie      Pages; Sandrine      Alibert-Franco; Abdallah      Mahamoud; Jean-Michel      Bolla; Anne      Davin-Regli; Jacqueline      Chevalier; Eric      Garnotel

Abstract

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.

Keywords: Multi-drug resistance (MDR), Efflux pump and drug transporters, AcrAB-TolC structure and function, Efflux pump inhibitors and blockers, Bacterial resistance modulators, Gram-Negative Bacteria, Antibiotic resistance mechanisms, multi-drug resistant, efflux pump inhibitor, (MDR), mutation of antibiotic targets, AcrA3-AcrB3-TolC3 com-plex, AcrB, MexB, tripartite efflux pump, TolC in E. coli, OprM in P. aeruginosa, structure-activity relationship, RND efflux pump, drug efflux systems, ß-lactam+ß-lactamase inhibitor association, 5'-methoxyhydnocarpin, antisense oligonucleotides, cmeA leader sequence, Globomycin, signal peptidase II, MexCD-OprJ pump, Polymyxins, antibiotic efflux duct, homotrimer (TolC3) channel, OMCs, Peptidomimetics, P. Aeruginosa Efflux System, (MexAB-OprM), fluoroquinolone, levofloxacin, naphthylamide, structure-activity rela-tionship study, AcrB trimer, amino acid residues, ß-lactam efflux, Quinoline Derivatives, quinolone, phenicol and cycline antibiotics, AcrB transporter, alkylaminoquinolines activity, PAßN activity, Arylpiperidines, Arylpiperazines, piperidine derivative, serotonin agonist, Phenothiazines, chlorpromazine, tetracycline analogues, Verapamil, reserpine, AcrB-MexB, m-chlorophenylhydra-zone, Gram-positive resistance modulators, hydrophobic alkaloid berberine, Mentha avensis, Lemongrass oil, terpenic compound, nitrocefin, Helichrysum italicum, amoxicillin-clavulanate, piperacillin/tazobactam