Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis

Ojo, Kayode K.; Ranade, Ranae M.; Zhang, Zhongsheng; Dranow, David M.; Myers, Janette B.; Choi, Ryan; Hewitt, Steve Nakazawa; Edwards, Thomas E.; Davies, Douglas R.; Lorimer, Donald; Boyle, Stephen M.; Barrett, Lynn K.; Buckner, Frederick S.; Fan, Erkang; Van Voorhis, Wesley C.; Gonzalez-Bello, Concepción

doi:10.1371/journal.pone.0160350

Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis

Journal Article · Mon Aug 08 00:00:00 EDT 2016 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0160350· OSTI ID:1329432

^[1]; Ranade, Ranae M. ^[1]; Zhang, Zhongsheng ^[1]; Dranow, David M. ^[2]; Myers, Janette B. ^[1]; Choi, Ryan ^[1]; Hewitt, Steve Nakazawa ^[1]; Edwards, Thomas E. ^[2]; Davies, Douglas R. ^[2]; Lorimer, Donald ^[2]; Boyle, Stephen M. ^[3]; Barrett, Lynn K. ^[1]; Buckner, Frederick S. ^[1]; Fan, Erkang ^[1]; Van Voorhis, Wesley C. ^[1]; Gonzalez-Bello, Concepción ^[4]

Univ. of Washington, Seattle, WA (United States)
Beryllium, Bainbridge Island, WA (United States)
Virginia Polytechnic Inst. and State Univ. (Virginia Tech), Blacksburg, VA (United States)
Univ. de Santiago de Compostela (Spain)

We investigated Brucella melitensis methionyl-tRNA-synthetase (BmMetRS) with molecular, structural and phenotypic methods to learn if BmMetRS is a promising target for brucellosis drug development. Recombinant BmMetRS was expressed, purified from wild type Brucella melitensis biovar Abortus 2308 strain ATCC/CRP #DD-156 and screened by a thermal melt assay against a focused library of one hundred previously classified methionyl-tRNA-synthetase inhibitors of the blood stage form of Trypanosoma brucei. Three compounds showed appreciable shift of denaturation temperature and were selected for further studies on inhibition of the recombinant enzyme activity and cell viability against wild type B. melitensis strain 16M. BmMetRS protein complexed with these three inhibitors resolved into three-dimensional crystal structures and was analyzed. All three selected methionyl-tRNA-synthetase compounds inhibit recombinant BmMetRS enzymatic functions in an aminoacylation assay at varying concentrations. Furthermore, growth inhibition of B. melitensis strain 16M by the compounds was shown. Inhibitor-BmMetRS crystal structure models were used to illustrate the molecular basis of the enzyme inhibition. Our current data suggests that BmMetRS is a promising target for brucellosis drug development. However, further studies are needed to optimize lead compound potency, efficacy and safety as well as determine the pharmacokinetics, optimal dosage, and duration for effective treatment.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health

OSTI ID:: 1329432

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 8 Vol. 11; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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aminoacylation
brucella
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crystal structure
drug research and development
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transfer RNA

Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis

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