title: Polyamino-Isoprenic Derivatives Block Intrinsic Resistance of P. aeruginosa to Doxycycline and Chloramphenicol In Vitro.
abstract: Multidrug resistant bacteria have been a worldwide concern for decades. Though new molecules that effectively target Gram-positive bacteria are currently appearing on the market, a gap remains in the treatment of infections caused by Gram-negative bacteria. Therefore, new strategies must be developed against these pathogens. The aim of this study was to select an antibiotic for which a bacterium is naturally resistant and to use an escort molecule to restore susceptibility, similarly to the model of β-lactam/ β-lactamase inhibitors. High-content screening was performed on the reference strain PA01, allowing the selection of four polyamino-isoprenic compounds that acted synergistically with doxycycline. They were assayed against clinical isolates and Multi-Drug-Resistant strains. One of these compounds was able to decrease the MIC of doxycycline on the reference strain, efflux pump overproducers and clinical isolates of P. aeruginosa, to the susceptibility level. Similar results were obtained using chloramphenicol as the antibiotic. Membrane permeation assays and real-time efflux experiments were used to characterize the mechanism of doxycycline potentiation. The results showed that the selected compound strongly decreases the efficiency of glucose-triggered efflux associated with a slight destabilization of the outer membrane. According to these data, targeting natural resistance may become an interesting way to combat MDR pathogens and could represent an alternative to already devised strategies.
authors.affiliation: Aix-Marseille Université, IRBA, TMCD2 UMR-MD1, Faculté de Médecine, 13385 Marseille, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Borselli
authors.affiliation: Aix-Marseille Université, IRBA, TMCD2 UMR-MD1, Faculté de Médecine, 13385 Marseille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Lieutaud
authors.affiliation: Aix-Marseille Université, IRBA, TMCD2 UMR-MD1, Faculté de Médecine, 13385 Marseille, France.|Hôpital d'Instruction des Armées Alphonse-Laveran, 13013 Marseille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Thefenne
authors.affiliation: Aix-Marseille Université, IRBA, TMCD2 UMR-MD1, Faculté de Médecine, 13385 Marseille, France.|Hôpital d'Instruction des Armées Alphonse-Laveran, 13013 Marseille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Garnotel
authors.affiliation: Aix-Marseille Université, IRBA, TMCD2 UMR-MD1, Faculté de Médecine, 13385 Marseille, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Pagès
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), CNRS, UMR7258, Institut Paoli Calmettes, Aix-Marseille Université, UM 105, Inserm, U1068, F-13009, Marseille, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Brunel
authors.affiliation: Aix-Marseille Université, IRBA, TMCD2 UMR-MD1, Faculté de Médecine, 13385 Marseille, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Bolla
mesh_terms: D002701:Chloramphenicol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects*
chemical_list: D002701:Chloramphenicol; D004318:Doxycycline