title: Indole Based Weapons to Fight Antibiotic Resistance: A Structure-Activity Relationship Study.
abstract: Antibiotic resistance represents a worldwide concern, especially regarding the outbreak of methicillin-resistant Staphylococcus aureus, a common cause for serious skin and soft tissues infections. A major contributor to Staphylococcus aureus antibiotic resistance is the NorA efflux pump, which is able to extrude selected antibacterial drugs and biocides from the membrane, lowering their effective concentrations. Thus, the inhibition of NorA represents a promising and challenging strategy that would allow recycling of substrate antimicrobial agents. Among NorA inhibitors, the indole scaffold proved particularly effective and suitable for further optimization. In this study, some unexplored modifications on the indole scaffold are proposed. In particular, for the first time, substitutions at the C5 and N1 positions have been designed to give 48 compounds, which were synthesized and tested against norA-overexpressing S. aureus. Among them, 4 compounds have NorA IC50 values lower than 5.0 μM proving to be good efflux pump inhibitor (EPI) candidates. In addition, preliminary data on their ADME (absorption, distribution, metabolism, and excretion) profile is reported.
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia , 06123 Perugia, Italy.
authors.forename: Susan
authors.initials: S
authors.lastname: Lepri
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia , 06123 Perugia, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Buonerba
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia , 06123 Perugia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Goracci
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia , 06123 Perugia, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Velilla
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia , 06123 Perugia, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Ruzziconi
authors.affiliation: The John D. Dingell Department of Veterans Affairs Medical Center , Detroit, Michigan 48201, United States.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Schindler
authors.affiliation: The John D. Dingell Department of Veterans Affairs Medical Center , Detroit, Michigan 48201, United States.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Seo
authors.affiliation: The John D. Dingell Department of Veterans Affairs Medical Center , Detroit, Michigan 48201, United States.|Department of Internal Medicine, Division of Infectious Diseases, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia , 06123 Perugia, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cruciani
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial / Q000187:drug effects*; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D007211:Indoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C075040:NorA protein, Staphylococcus