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

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.

Jirgensons, A. (author)
Varik, ValloUmeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia(Swepub:umu)vava0008 (author)
Hauryliuk, VVasiliUmeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia(Swepub:umu)vaha0006 (author)
Goessens, W. H. F. (author)
Hays, J. P. (author)
Umeå universitetMolekylär Infektionsmedicin, Sverige (MIMS) (creator_code:org_t)

In:European Journal of Clinical Microbiology and Infectious Diseases: Springer Science and Business Media LLC35:11, s. 1857-18640934-97231435-4373

By the author/editor: Monteferrante, C ...; Jirgensons, A.; Varik, Vallo; Hauryliuk, VVasi ...; Goessens, W. H. ...; Hays, J. P.

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Microbiology in ...

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