title: Anthelmintic closantel enhances bacterial killing of polymyxin B against multidrug-resistant Acinetobacter baumannii.
abstract: Polymyxins, an old class of antibiotics, are currently used as the last resort for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii. However, recent pharmacokinetic and pharmacodynamic data indicate that monotherapy can lead to the development of resistance. Novel approaches are urgently needed to preserve and improve the efficacy of this last-line class of antibiotics. This study examined the antimicrobial activity of novel combination of polymyxin B with anthelmintic closantel against A. baumannii. Closantel monotherapy (16 mg l(-1)) was ineffective against most tested A. baumannii isolates. However, closantel at 4-16 mg l(-1) with a clinically achievable concentration of polymyxin B (2 mg l(-1)) successfully inhibited the development of polymyxin resistance in polymyxin-susceptible isolates, and provided synergistic killing against polymyxin-resistant isolates (MIC ⩾4 mg l(-1)). Our findings suggest that the combination of polymyxin B with closantel could be potentially useful for the treatment of MDR, including polymyxin-resistant, A. baumannii infections. The repositioning of non-antibiotic drugs to treat bacterial infections may significantly expedite discovery of new treatment options for bacterial 'superbugs'.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors.forename: Thien B
authors.initials: TB
authors.lastname: Tran
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors.forename: Soon-Ee
authors.initials: SE
authors.lastname: Cheah
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Yu
authors.affiliation: Centre for Medicine Use and Safety, Monash University, Melbourne, Australia.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Bergen
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Creek
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Science, Monash University, Melbourne, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Purcell
authors.affiliation: School of Pharmacy, University at Buffalo, Buffalo, NY, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Doi
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Science, Monash University, Melbourne, Australia.
authors.forename: Jiangning
authors.initials: J
authors.lastname: Song
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Velkov
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000382:microbiology; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000871:Anthelmintics / Q000008:administration & dosage / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D058492:Drug Repositioning; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000008:administration & dosage / Q000494:pharmacology*; D012458:Salicylanilides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000871:Anthelmintics; D000900:Anti-Bacterial Agents; D012458:Salicylanilides; C023342:closantel; D011112:Polymyxin B