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

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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. Althoughwedetectnosynergyorantagonismincombination 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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Judul Seri

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No. Panggil

artikel

Penerbit

USA : Springer., 2016

Deskripsi Fisik

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Bahasa

English

ISBN/ISSN

DOI 10.1007/s10096-0

Klasifikasi

NONE

Tipe Isi

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Tipe Media

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Tipe Pembawa

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Edisi

Eur J Clin Microbiol Infect Dis (2016) 35:1857–186

Subjek

Medicine
characteristics of leucyl-tRNA synthetase

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