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Evaluation of the characteristics of leucyl-tRNA synthetase (LeuRS) inhibitor AN3365 in combination with different antibiotic classes

Monteferrante, C. G. ; Jirgensons, A. ; Varik, V. ; Hauryliuk, V. LU orcid ; Goessens, W. H.F. and Hays, J. P. (2016) In European Journal of Clinical Microbiology and Infectious Diseases 35. p.1857-1864
Abstract

Aminoacyl tRNA synthetases are enzymes involved in the key process of coupling an amino acid to its cognate tRNA. AN3365 is a novel antibiotic that specifically targets leucyl-tRNA synthetase, whose development was halted after evaluation in phase II clinical trials owing to the rapid selection of resistance. In an attempt to bring AN3365 back into the developmental pipeline we have evaluated the efficacy of AN3365 in combination with different classes of antibiotic and characterized its mechanism of action. Although we detect no synergy or antagonism in combination with a range of antibiotic classes, a combination of AN3365 with colistin reduces the accumulation of AN3365-resistant and colistin resistance mutations. We also demonstrate... (More)

Aminoacyl tRNA synthetases are enzymes involved in the key process of coupling an amino acid to its cognate tRNA. AN3365 is a novel antibiotic that specifically targets leucyl-tRNA synthetase, whose development was halted after evaluation in phase II clinical trials owing to the rapid selection of resistance. In an attempt to bring AN3365 back into the developmental pipeline we have evaluated the efficacy of AN3365 in combination with different classes of antibiotic and characterized its mechanism of action. Although we detect no synergy or antagonism in combination with a range of antibiotic classes, a combination of AN3365 with colistin reduces the accumulation of AN3365-resistant and colistin resistance mutations. We also demonstrate that treatment with AN3365 results in the dramatic accumulation of the alarmone (p)ppGpp, the effector of the stringent response—a key player in antibiotic tolerance.

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publishing date
type
Contribution to journal
publication status
published
in
European Journal of Clinical Microbiology and Infectious Diseases
volume
35
pages
1857 - 1864
publisher
Springer
external identifiers
  • scopus:84981170539
  • pmid:27506217
ISSN
0934-9723
DOI
10.1007/s10096-016-2738-1
language
English
LU publication?
no
additional info
Funding Information: This work was supported by a grant from the European Union Framework 7 (FP7) programme—Health.2013.2.31-1- NABARSI (grant agreement no: 601725— www.nabarsi.eu ). Publisher Copyright: © 2016, The Author(s). Copyright: Copyright 2017 Elsevier B.V., All rights reserved.
id
5de2204f-3491-4655-baeb-e10c243ed4ca
date added to LUP
2021-09-24 20:42:03
date last changed
2024-06-15 17:35:15
@article{5de2204f-3491-4655-baeb-e10c243ed4ca,
  abstract     = {{<p>Aminoacyl tRNA synthetases are enzymes involved in the key process of coupling an amino acid to its cognate tRNA. AN3365 is a novel antibiotic that specifically targets leucyl-tRNA synthetase, whose development was halted after evaluation in phase II clinical trials owing to the rapid selection of resistance. In an attempt to bring AN3365 back into the developmental pipeline we have evaluated the efficacy of AN3365 in combination with different classes of antibiotic and characterized its mechanism of action. Although we detect no synergy or antagonism in combination with a range of antibiotic classes, a combination of AN3365 with colistin reduces the accumulation of AN3365-resistant and colistin resistance mutations. We also demonstrate that treatment with AN3365 results in the dramatic accumulation of the alarmone (p)ppGpp, the effector of the stringent response—a key player in antibiotic tolerance.</p>}},
  author       = {{Monteferrante, C. G. and Jirgensons, A. and Varik, V. and Hauryliuk, V. and Goessens, W. H.F. and Hays, J. P.}},
  issn         = {{0934-9723}},
  language     = {{eng}},
  pages        = {{1857--1864}},
  publisher    = {{Springer}},
  series       = {{European Journal of Clinical Microbiology and Infectious Diseases}},
  title        = {{Evaluation of the characteristics of leucyl-tRNA synthetase (LeuRS) inhibitor AN3365 in combination with different antibiotic classes}},
  url          = {{http://dx.doi.org/10.1007/s10096-016-2738-1}},
  doi          = {{10.1007/s10096-016-2738-1}},
  volume       = {{35}},
  year         = {{2016}},
}