In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics

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...

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Main Authors:	Bruhn, David F., Scherman, Michael S., Liu, Jiuyu, Scherbakov, Dimitri, Meibohm, Bernd, Böttger, Erik C., Lenaerts, Anne J., Lee, Richard E.
Format:	Online
Language:	English
Published:	Nature Publishing Group 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568539/

id	pubmed-4568539
recordtype	oai_dc
spelling	pubmed-45685392015-09-23 In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics Bruhn, David F. Scherman, Michael S. Liu, Jiuyu Scherbakov, Dimitri Meibohm, Bernd Böttger, Erik C. Lenaerts, Anne J. Lee, Richard E. Article 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. Nature Publishing Group 2015-09-14 /pmc/articles/PMC4568539/ /pubmed/26365087 http://dx.doi.org/10.1038/srep13985 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Bruhn, David F. Scherman, Michael S. Liu, Jiuyu Scherbakov, Dimitri Meibohm, Bernd Böttger, Erik C. Lenaerts, Anne J. Lee, Richard E.
spellingShingle	Bruhn, David F. Scherman, Michael S. Liu, Jiuyu Scherbakov, Dimitri Meibohm, Bernd Böttger, Erik C. Lenaerts, Anne J. Lee, Richard E. In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics
author_facet	Bruhn, David F. Scherman, Michael S. Liu, Jiuyu Scherbakov, Dimitri Meibohm, Bernd Böttger, Erik C. Lenaerts, Anne J. Lee, Richard E.
author_sort	Bruhn, David F.
title	In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics
title_short	In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics
title_full	In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics
title_fullStr	In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics
title_full_unstemmed	In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics
title_sort	in vitro and in vivo evaluation of synergism between anti-tubercular spectinamides and non-classical tuberculosis antibiotics
description	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.
publisher	Nature Publishing Group
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568539/
_version_	1613475328284426240

In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics

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