title: A New Combination of a Pleuromutilin Derivative and Doxycycline for Treatment of Multidrug-Resistant Acinetobacter baumannii.
abstract: Multidrug-resistant (MDR) Acinetobacter baumannii is one of the most difficult Gram-negative bacteria to treat and eradicate. In a cell-based screening of pleuromutilin derivatives against a drug sensitive A. baumannii strain, new molecules (2-4) exhibit bacteriostatic activity with 3.13 μg/mL concentration and 1 shows bactericidal activity with an MBC of 6.25 μg/mL. The pleuromutilin derivative 1 displays strong synergistic effects with doxycycline in a wide range of concentrations. A 35/1 ratio of 1 and doxycycline (1-Dox 35/1) kills drug susceptible A. baumannii with the MBC of 2.0 μg/mL and an MDR A. baumannii with the MBC of 3.13 μg/mL. In vitro anti-Acinetobacter activity of 1-Dox 35/1 is superior to that of clinical drugs such as tobramycin, tigecycline, and colistin. The efficacy of 1-Dox 35/1 is evaluated in a mouse septicemia model; treatment of the infected C57BL/6 mice with 1-Dox 35/1 protects from lethal infection of A. baumannii with an ED50value of <2.0 mg/kg.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
authors.forename: Shajila
authors.initials: S
authors.lastname: Siricilla
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mitachi
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota , 205 VSB, 1971 Commonwealth Avenue, St. Paul, Minnesota 55108, United States.
authors.forename: Junshu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
authors.forename: Shakiba
authors.initials: S
authors.lastname: Eslamimehr
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
authors.forename: Maddie R
authors.initials: MR
authors.lastname: Lemieux
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
authors.forename: Bernd
authors.initials: B
authors.lastname: Meibohm
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota , 205 VSB, 1971 Commonwealth Avenue, St. Paul, Minnesota 55108, United States.
authors.forename: Yinduo
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center , 881 Madison Avenue, Memphis, Tennessee 38163, United States.
authors.forename: Michio
authors.identifier: 0000-0003-0092-0619
authors.initials: M
authors.lastname: Kurosu
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy*; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004318:Doxycycline / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011083:Polycyclic Compounds; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D004224:Diterpenes; D004318:Doxycycline; D011083:Polycyclic Compounds; D000097567:Pleuromutilins