title: In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics.
abstract: Spectinamides are new semi-synthetic spectinomycin derivatives with potent anti-tubercular activity. The reported synergism of the precursor spectinomycin with other antibiotics prompted us to examine whether spectinamides sensitize M. tuberculosis to other antibiotics not traditionally used in the treatment of tuberculosis to potentially expand therapeutic options for MDR/XDR Tuberculosis. Whole cell synergy checkerboard screens were performed using the laboratory strain M. tuberculosis H37Rv, lead spectinamide 1599, and a broad panel of 27 antibiotics. In vitro, 1599 synergized with 11 drugs from 6 antibiotic classes. The observed synergy was tested against clinical isolates confirming synergy with Clarithromycin, Doxycycline and Clindamycin, combinations of which were taken forward for in vivo efficacy determination. Co-administration of 1599 and clarithromycin provided additional bacterial killing in a mouse model of acute tuberculosis infection, but not in a chronic infection model. Further studies indicated that mismatched drug exposure profiles likely permitted induction of phenotypic clarithromycin resistance and subsequent loss of synergism. These studies highlight the importance of validating in vitro synergism and the challenge of matching drug exposures to obtain a synergistic outcome in vivo. Results from this study indicate that a 1599 clarithromycin combination is potentially viable, providing the drug exposures can be carefully monitored.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Bruhn
authors.affiliation: Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Scherman
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jiuyu
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Scherbakov
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Meibohm
authors.affiliation: Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
authors.affiliation: Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000208:Acute Disease; D000818:Animals; D000995:Antitubercular Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D017291:Clarithromycin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D002981:Clindamycin / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004318:Doxycycline / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004357:Drug Synergism; D006207:Half-Life; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D002981:Clindamycin; D017291:Clarithromycin; D004318:Doxycycline